Proteasome inhibitors

ABSTRACT

Disclosed herein are compounds of Formula (I) that include a sulfonate ester, ester or ether group. Compounds of Formula (I) can be included in pharmaceutical compositions, and can be used to treating and/or ameliorating a disease or condition, such as cancer, a microbial disease and/or inflammation.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a divisional of U.S. application Ser. No.12/464,686, entitled “PROTEASOME INHIBITORS,” filed May 12, 2009, nowU.S. Pat. No. 7,910,616, which claims priority to U.S. ProvisionalPatent Application No. 61/052,576, entitled “PROTEASOME INHIBITORS”filed May 12, 2008, which is incorporated herein by reference in itsentirety, including any drawings.

BACKGROUND

1. Field

The present application relates to certain compounds and to methods forthe preparation of certain compounds that can be used in the fields ofchemistry and medicine.

2. Description

Cancer is a leading cause of death in the United States. Despitesignificant efforts to find new approaches for treating cancer, theprimary treatment options remain surgery, chemotherapy and radiationtherapy, either alone or in combination. Surgery and radiation therapy,however, are generally useful only for fairly defined types of cancer,and are of limited use for treating patients with disseminated disease.Chemotherapy is the method that is generally useful in treating patientswith metastatic cancer or diffuse cancers such as leukemias. Althoughchemotherapy can provide a therapeutic benefit, it often fails to resultin cure of the disease due to the patient's cancer cells becomingresistant to the chemotherapeutic agent. Due, in part, to the likelihoodof cancer cells becoming resistant to a chemotherapeutic agent, suchagents are commonly used in combination to treat patients.

Similarly, infectious diseases caused, for example, by bacteria, fungiand protozoa are becoming increasingly difficult to treat and cure. Forexample, more and more bacteria, fungi and protozoa are developingresistance to current antibiotics and chemotherapeutic agents. Examplesof such microbes include Bacillus, Leishmania, Plasmodium andTrypanosoma.

Furthermore, a growing number of diseases and medical conditions areclassified as inflammatory diseases. Such diseases include conditionssuch as asthma to cardiovascular diseases. These diseases continue toaffect larger and larger numbers of people worldwide despite newtherapies and medical advances.

Therefore, a need exists for additional chemotherapeutics,anti-microbial agents, and anti-inflammatory agents to treat cancer,inflammatory diseases and infectious disease. A continuing effort isbeing made by individual investigators, academia and companies toidentify new, potentially useful chemotherapeutic and anti-microbialagents.

Marine-derived natural products are a rich source of potential newanti-cancer agents and anti-microbial agents. The oceans are massivelycomplex and house a diverse assemblage of microbes that occur inenvironments of extreme variations in pressure, salinity, andtemperature. Marine microorganisms have therefore developed uniquemetabolic and physiological capabilities that not only ensure survivalin extreme and varied habitats, but also offer the potential to producemetabolites that would not be observed from terrestrial microorganisms(Okami, Y. 1993 J Mar Biotechnol 1:59). Representative structuralclasses of such metabolites include terpenes, peptides, polyketides, andcompounds with mixed biosynthetic origins. Many of these molecules havedemonstrable anti-tumor, anti-bacterial, anti-fungal, anti-inflammatoryor immunosuppressive activities (Bull, A. T. et al. 2000 Microbiol MolBiol Rev 64:573; Cragg, G. M. & D. J. Newman 2002 Trends Pharmacol Sci23:404; Kerr, R. G. & S. S. Kerr 1999 Exp Opin Ther Patents 9:1207;Moore, B. S 1999 Nat Prod Rep 16:653; Faulkner, D. J. 2001 Nat Prod Rep18:1; Mayer, A. M. & V. K. Lehmann 2001 Anticancer Res 21:2489),validating the utility of this source for isolating invaluabletherapeutic agents. Further, the isolation of novel anti-cancer andanti-microbial agents that represent alternative mechanistic classes tothose currently on the market will help to address resistance concerns,including any mechanism-based resistance that may have been engineeredinto pathogens for bioterrorism purposes.

SUMMARY

The embodiments disclosed herein generally relate compounds, includingheterocyclic compounds and analogs thereof that include a sulfonateester, carboxylic ester or ether group. Some embodiments are directed tothe chemical compounds and pharmaceutical compositions that contain oneor more chemical compounds. Other embodiments are directed to methods ofsynthesizing the chemical compounds. Still other embodiments aredirected to methods of treating and/or ameliorating a disease orconditions with one or more chemical compounds or a pharmaceuticalcomposition that contains one or more chemical compounds.

Some embodiments disclosed herein relate to a compound of Formula (I),or pharmaceutically acceptable salt, ester or prodrug thereof:

wherein R¹, R², R³, E¹, E², E³, E⁴. E⁵ and n are described herein.

Other embodiments described herein relate to a method of synthesizing acompound of Formula (I) that includes reacting a compound of Formula (A)with a silver reagent, such as AgF or AgF—CaF₂, to form a compound ofFormula (B), and then reacting the compound of Formula (B) with

to form a compound of Formula (I). The variables R¹, R², R³, E¹, E², E³,E⁴. E⁵, R^(A), R^(B), R^(D), E^(A), E^(B), E^(D), E^(E). E^(E), X^(A),X^(B), R^(C), n and m.

Some embodiments described herein relate to a pharmaceutical compositionthat can include one or more compounds described herein, such as acompound of Formula (I), or pharmaceutically acceptable salt, ester orprodrug thereof, and one or more selected from a diluent, an excipientand a carrier.

Another embodiment described herein relates to a method for treating,alleviating or diagnosing a neoplastic disease that can includeadministering to a subject a therapeutically effective amount of one ormore compounds described herein (for example, a compound of Formula(I)), or pharmaceutically acceptable salt, ester or prodrug thereof, ora pharmaceutical composition described herein, such as a pharmaceuticalcomposition that includes one or more compounds of Formula (I).

Other embodiments described herein relate to a method for inhibiting thegrowth of a cancer cell that can include contacting the cancer cell withan effective amount of one or more compounds described herein, such as acompound of Formula (I), or pharmaceutically acceptable salt, ester orprodrug thereof, or a pharmaceutical composition that includes one ormore compounds of Formula (I).

An embodiment described herein relates to a method for inhibitingproteasome activity that can include contacting a cell with an effectiveamount of one or more compounds described herein, such as a compound ofFormula (I), or pharmaceutically acceptable salt, ester or prodrugthereof, or a pharmaceutical composition that includes one or morecompounds of Formula (I).

Some embodiments described herein relate to a method for inhibitingNF-κB activation that can include contacting a cell with an effectiveamount of one or more compounds described herein (for example, acompound of Formula (I)), or pharmaceutically acceptable salt, ester orprodrug thereof, or a pharmaceutical composition that includes one ormore compounds of Formula (I).

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows a graph of the results of a dialysis experiment in the 20Sproteasome of several compound of Formula (I).

DETAILED DESCRIPTION

Numerous references are cited herein. The references cited herein,including the U.S. patents cited herein, are each to be consideredincorporated by reference in their entirety into this specification.

Salinosporamide A and its analogs thereof have various biologicalactivities. The structure of Salinosporamide A is shown below.

Studies have been conducted that show Salinosporamide A and its analogshave proteasome inhibitory activity, effect NF-κB/IκB signaling pathway,and have anti-anthrax activity. Salinosporamide A and several analogs,as well as biological activity of the same, are described in U.S.Provisional Patent Application Nos. 60/480,270, filed Jun. 20, 2003;60/566,952, filed Apr. 30, 2004; 60/627,461, filed Nov. 12, 2004;60/633,379, filed Dec. 3, 2004; 60/643,922, filed Jan. 13, 2005;60/658,884, filed Mar. 4, 2005; 60/676,533, filed Apr. 29, 2005;60/567,336, filed Apr. 30, 2004; 60/580,838, filed Jun. 18, 2004;60/591,190, filed Jul. 26, 2004; 60/627,462, filed Nov. 12, 2004;60/644,132, filed Jan. 13, 2005; 60/659,385, filed Mar. 4, 2005;61/034,900, filed Mar. 7, 2008 and 61/073,545, filed Jun. 18, 2008; U.S.patent application Ser. Nos. 10/871,368, filed Jun. 18, 2004;11/118,260, filed Apr. 29, 2005; 11/412,476, filed Apr. 27, 2006;11/453,374, filed Jun. 15, 2006; 11/865,704, filed Oct. 1, 2007;11/697,689, filed Apr. 6, 2007; 12/136,688, filed Jun. 10, 2008 and12/399,382, filed Mar. 6, 2009; and International Patent ApplicationNos. PCT/US2004/019543, filed Jun. 18, 2004; PCT/US2005/044091, filedDec. 2, 2005; PCT/US2005/014846, filed Apr. 29, 2005; PCT/US2006/016104,filed Apr. 27, 2006; PCT/US2007/008562, filed Apr. 6, 2007;PCT/US2009/036376, filed Mar. 6, 2009; each of which is herebyincorporated by reference in its entirety.

Disclosed herein analogs of Salinosporamide A that include a sulfonateester, carboxylic ester or ether group. Also disclosed herein arepharmaceutical compositions that include one or more of theSalinosporamide A analogs with a sulfonate ester, carboxylic ester orether group, methods of making Salinosporamide A analogs with asulfonate ester, carboxylic ester or ether group and methods of usingSalinosporamide A analogs with a sulfonate ester, carboxylic ester orether group for treating and/or ameliorating a disease or condition suchas cancer, a microbial disease and/or inflammation. In some embodiments,analogs of Salinosporamide A can include a bulky sulfonate ester, abulky carboxylic ester or a bulky ether group. In an embodiment, analogsof Salinosporamide A that include a bulky sulfonate ester, a bulkycarboxylic ester or a bulky ether group have improved inhibition of thecaspase activity.

Unless otherwise indicated, when a substituent is deemed to be“optionally substituted,” or “substituted” it is meant that theindicated group may be substituted with one or more group(s)individually and independently selected from alkyl, alkenyl, alkynyl,alkoxy, cycloalkyl, cycloalkenyl, cycloalkynyl, acyl, acylamino,acyloxy, amino, mono-substituted amine, di-substituted amine, alkylamino, aminoacyl, aminoacyloxy, oxyacylamino, halogen, mono-haloalkyl,di-haloalkyl, tri-haloalkyl, mono-haloalkoxy, di-haloalkoxy,tri-haloalkoxy, hydroxy, carboxylalkyl, thioketo, thiol, thioalkoxy,aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclic, heterocyclooxy,hydroxyamino, alkoxyamino, nitro, —SO-alkyl, —SO-substituted alkyl,—SO-aryl, —SO-hetero aryl, —SO₂—H, —SO₂—OH, —SO₂-alkyl, —SO₂-aryl and—SO₂-heteroaryl, boronate alkyl, boronic acid, (OH)₂B-alkyl, phosphateand phosphate esters, phosphonooxy, phosphonooxyalkyl, azido,azidoalkyl, ammonium, aminoalkyl, salt of an aminoalkyl, carboxyalkyl, asalt of a carboxyalkyl, alkylamino, a salt of an alkylamino,dialkylamino, a salt of a dialkylamino, alkylthio, arylthio, carboxy,cyano, alkoxysulfinyl, thiocyano, boronic acidalkyl, boronic esteralkyl,sulfoalkyl, a salt of a sulfoalkyl, alkoxysulfonylalkyl, sulfooxyalkyl,a salt of a sulfooxyalkyl, alkoxysulfonyloxyalkyl, phosphonooxyalkyl, asalt of a phosphonooxyalkyl, (alkylphosphooxy)alkyl, phosphorylalkyl, asalt of a phosphorylalkyl, (alkylphosphoryl)alkyl, pyridinylalkyl, asalt of a pyridinylalkyl, a salt of a heteroarylalkyl guanidino, a saltof a guanidino, and guanidinoalkyl.

Whenever a group is described as “optionally substituted” the group maybe unsubstituted or substituted with one or more substituents asdescribed herein.

As used herein, any “R” group(s) such as, without limitation, R, R¹, R²,R³, R⁴, R⁵, R⁶, R⁷, R⁸, R^(a), R^(b), R^(A), R^(B) and R^(C) representsubstituents that can be attached to the indicated atom. An R group maybe substituted or unsubstituted. If two “R” groups are covalently bondedto the same atom or to adjacent atoms, then they may be “taken together”as defined herein to form a cycloalkyl, aryl, heteroaryl or heterocycle.For example, without limitation, if R^(1a) and R^(1b) of anNR^(1a)R^(1b) group are indicated to be “taken together,” it means thatthey are covalently bonded to one another to form a ring:

As used herein, “C_(m) to C_(n),” in which “m” and “n” are integersrefers to the number of carbon atoms in an alkyl, alkenyl or alkynylgroup or the number of carbon atoms in the ring of a cycloalkyl,cycloalkenyl, cycloalkynyl, aryl, heteroaryl or heteroalicyclyl group.That is, the alkyl, alkenyl, alkynyl, ring of the cycloalkyl, ring ofthe cycloalkenyl, ring of the cycloalkynyl, ring of the aryl, ring ofthe heteroaryl or ring of the heteroalicyclyl can contain from “m” to“n”, inclusive, carbon atoms. Thus, for example, a “C₁ to C₄ alkyl”group refers to all alkyl groups having from 1 to 4 carbons, that is,CH₃—, CH₃CH₂—, CH₃CH₂CH₂—, (CH₃)₂CH—, CH₃CH₂CH₂CH₂—, CH₃CH₂CH(CH₃)— and(CH₃)₃C—. If no “m” and “n” are designated with regard to an alkyl,alkenyl, alkynyl, cycloalkyl cycloalkenyl, cycloalkynyl, aryl,heteroaryl or heteroalicyclyl group, the broadest range described inthese definitions is to be assumed. Whenever it appears herein, anumerical range such as “1 to 20” refers to each integer in the givenrange. For example, “1 to 20 carbon atoms” means that the indicatedgroup may consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms,etc., up to and including 20 carbon atoms.

The term “alkyl,” as used herein, means any unbranched or branched,substituted or unsubstituted, saturated hydrocarbon, with C₁-C₂₄preferred, and C₁-C₆ hydrocarbons being preferred, with methyl, ethyl,propyl, isopropyl, butyl, isobutyl, and tert-butyl, and pentyl beingmost preferred.

The term “alkenyl,” as used herein, means any unbranched or branched,substituted or unsubstituted, unsaturated hydrocarbon containing one ormore double bonds. Some examples of alkenyl groups include allyl,homo-allyl, vinyl, crotyl, butenyl, pentenyl, hexenyl, heptenyl andoctenyl.

The term “alkynyl” as used herein, means any unbranched or branched,substituted or unsubstituted, unsaturated hydrocarbon with one or moretriple bonds

As used herein, “cycloalkyl” refers to a completely saturated (no doubleor triple bonds) mono- or multi-cyclic hydrocarbon ring system. Whencomposed of two or more rings, the rings may be joined together in afused fashion. Cycloalkyl groups can contain 3 to 10 atoms in thering(s) or 3 to 8 atoms in the ring(s). A cycloalkyl group may beunsubstituted or substituted. Typical cycloalkyl groups include, but arein no way limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,and the like.

As used herein, “cycloalkenyl” refers to a mono- or multi-cyclichydrocarbon ring system that contains one or more double bonds in atleast one ring; although, if there is more than one, the double bondscannot form a fully delocalized pi-electron system throughout all therings (otherwise the group would be “aryl,” as defined herein). Whencomposed of two or more rings, the rings may be connected together in afused fashion. A cycloalkenyl group may be unsubstituted or substituted.

As used herein, “cycloalkynyl” refers to a mono- or multi-cyclichydrocarbon ring system that contains one or more triple bonds in atleast one ring. If there is more than one triple bond, the triple bondscannot form a fully delocalized pi-electron system throughout all therings. When composed of two or more rings, the rings may be joinedtogether in a fused fashion. A cycloalkynyl group may be unsubstitutedor substituted.

The term “acyl” refers to hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl,cycloalkenyl, cycloalkynyl, aryl, heteroaryl or heterocyclyl connected,as substituents, via a carbonyl group. Examples include formyl, acetyl,propanoyl, benzoyl, and acryl. An acyl may be substituted orunsubstituted.

The term “carboxy” group refers to a “—C(═O)OR” group in which R can behydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl,cycloalkynyl, aryl, heteroaryl or heterocyclyl. A carboxy may besubstituted or unsubstituted.

As used herein, “aryl” refers to a hydrocarbon monocyclic or multicyclicaromatic ring system that has a fully delocalized pi-electron systemthroughout all the rings. The number of carbon atoms in an aryl groupcan vary. For example, the aryl group can be a C₆-C₁₄ aryl group, aC₆-C₁₀ aryl group, or a C₆ aryl group. Moreover, the term “aryl”includes fused ring systems wherein two carbocyclic rings share leastone chemical bond. Some examples of “aryl” rings include optionallysubstituted phenyl, naphthalenyl, phenanthrenyl and anthracenyl. An arylgroup may be substituted or unsubstituted.

As used herein, “heteroaryl” refers to a monocyclic or multicyclicaromatic ring system (a ring system with fully delocalized pi-electronsystem) that contain(s) one or more heteroatoms, that is, an elementother than carbon, including but not limited to, nitrogen, oxygen andsulfur. The number of atoms in the ring(s) of a heteroaryl group canvary. For example, the heteroaryl group can contain 4 to 14 atoms in thering(s), 5 to 10 atoms in the ring(s) or 5 to 6 atoms in the ring(s).Furthermore, the term “heteroaryl” includes fused ring systems where tworings, such as at least one aryl ring and at least one heteroaryl ring,or at least two heteroaryl rings, share at least one chemical bond. Aheteroaryl can be substituted or unsubstituted. A non-limiting list ofexamples of heteroaryls include furan, thiophene, phthalazine, pyrrole,oxazole, thiazole, imidazole, pyrazole, isoxazole, isothiazole,triazole, thiadiazole, pyridine, pyridazine, pyrimidine, pyrazine,triazine, benzofuran, benzothiopene and quinoline.

The terms “heterocycle” and “heterocyclyl” are intended to mean three-,four-, five-, six-, seven-, eight-, nine-, ten-, up to 18-memberedmonocyclic, bicyclic, and tricyclic ring system wherein carbon atomstogether with from 1 to 5 heteroatoms constitute said ring system. Aheterocycle may optionally contain one or more unsaturated bondssituated in such a way, however, that a fully delocalized pi-electronsystem does not occur throughout all the rings. The heteroatoms areindependently selected from oxygen, sulfur, and nitrogen. A heterocyclemay further contain one or more carbonyl or thiocarbonylfunctionalities, so as to make the definition include oxo-systems andthio-systems such as lactams, lactones, cyclic imides, cyclicthioimides, cyclic carbamates, and the like. When composed of two ormore rings, the rings may be joined together in a fused fashion.Examples of benzo-fused heterocyclyl groups include, but are not limitedto, benzimidazolidinone, tetrahydroquinoline, and methylenedioxybenzenering structures. Some examples of heterocyclyls include, but are notlimited to, tetrahydrothiopyran, 4H-pyran, tetrahydropyran, piperidine,1,3-dioxin, 1,3-dioxane, 1,4-dioxin, 1,4-dioxane, piperazine,1,3-oxathiane, 1,4-oxathiin, 1,4-oxathiane, tetrahydro-1,4-thiazine,2H-1,2-oxazine, maleimide, succinimide, barbituric acid, thiobarbituricacid, dioxopiperazine, hydantoin, dihydrouracil, morpholine, trioxane,hexahydro-1,3,5-triazine, tetrahydrothiophene, tetrahydrofuran,pyridine, pyridinium, pyrroline, pyrrolidine, pyrrolidone, pyrrolidione,pyrazoline, pyrazolidine, imidazoline, imidazolidine, 1,3-dioxole,1,3-dioxolane, 1,3-dithiole, 1,3-dithiolane, isoxazoline, isoxazolidine,oxazoline, oxazolidine, oxazolidinone, thiazoline, thiazolidine, and1,3-oxathiolane. A heterocycle group may be substituted orunsubstituted.

The term “alkoxy” refers to any unbranched, or branched, substituted orunsubstituted, saturated or unsaturated ether. In some embodiments, thealkoxy is an unbranched or branched alkyl group connected to theindicated group via an oxygen atom. Examples of alkoxy groups includemethoxy, ethoxy, isopropoxy, tert-butoxy and the like.

The term “(cycloalkyl)alkyl is understood as a cycloalkyl groupconnected, as a substituent, via a lower alkylene. The (cycloalkyl)alkylgroup and lower alkylene of a (cycloalkyl)alkyl group may be substitutedor unsubstituted.

The terms “(heterocycle)alkyl” and “(heterocyclyl)alkyl” are understoodas a heterocycle group connected, as a substituent, via a loweralkylene. The heterocycle group and the lower alkylene of a(heterocycle)alkyl group may be substituted or unsubstituted.

The term “arylalkyl” is intended to mean an aryl group connected, as asubstituent, via a lower alkylene, each as defined herein. The arylgroup and lower alkylene of an arylalkyl may be substituted orunsubstituted. Examples include benzyl, substituted benzyl,2-phenylethyl, 3-phenylpropyl, and naphthylalkyl.

The term “heteroarylalkyl” is understood as heteroaryl groups connected,as substituents, via a lower alkylene, each as defined herein. Theheteroaryl and lower alkylene of a heteroarylalkyl group may besubstituted or unsubstituted. Examples include 2-thienylmethyl,3-thienylmethyl, furylmethyl, thienylethyl, pyrrolylalkyl, pyridylalkyl,isoxazolylalkyl, imidazolylalkyl, and their substituted as well asbenzo-fused analogs.

The term “halogen atom,” as used herein, means any one of theradio-stable atoms of column 7 of the Periodic Table of the Elements,i.e., fluorine, chlorine, bromine, or iodine, with bromine and chlorinebeing preferred.

As used herein, the term “mono-substituted amine” refers to a “—NHR”group, wherein R can be alkyl, alkenyl, alkynyl, cycloalkyl,cycloalkenyl, cycloalkynyl, aryl, heteroaryl or heterocyclyl. Amono-substituted amine may be substituted or unsubstituted.

As used herein, the term “di-substituted amine” refers to a “—NR′R′”group, wherein each R′ can be independently alkyl, alkenyl, alkynyl,cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl orheterocyclyl. A di-substituted amine may be substituted orunsubstituted.

As employed herein, the following terms have their accepted meaning inthe chemical literature.

ACN acetonitrile

C-L caspase-like

CT-L chymotrypsin-like

DCC N,N′-dicyclohexylcarbodiimide

DMAP 4-(dimethylamino)pyridine

DMSO dimethylsulfoxide

EDC 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide

EDTA ethylenediaminetetraacetic acid

EtOAc ethyl acetate

HPLC high performance liquid chromatography

HRESIMS high-resolution mass spectrometry

TFA trifluoroacetic acid

THF tetrahydrofuran

T-L trypsin-like

The terms “protecting group moiety” and “protecting group moieties” asused herein refer to any atom or group of atoms that is added to amolecule in order to prevent existing groups in the molecule fromundergoing unwanted chemical reactions. Examples of protecting groupmoieties are described in T. W. Greene and P. G. M. Wuts, ProtectiveGroups in Organic Synthesis, 3. Ed. John Wiley & Sons, 1999, and in J.F. W. McOmie, Protective Groups in Organic Chemistry Plenum Press, 1973,both of which are hereby incorporated by reference. The protecting groupmoiety may be chosen in such a way, that they are stable to the reactionconditions applied and readily removed at a convenient stage usingmethodology known from the art. A non-limiting list of protecting groupsinclude benzyl; substituted benzyl; alkylcarbonyls (e.g.,t-butoxycarbonyl (BOC)); arylalkylcarbonyls (e.g., benzyloxycarbonyl,benzoyl); substituted methyl ether (e.g. methoxymethyl ether);substituted ethyl ether; a substituted benzyl ether; tetrahydropyranylether; silyl ethers (e.g., trimethylsilyl, triethylsilyl,triisopropylsilyl, t-butyldimethylsilyl, or t-butyldiphenylsilyl);esters (e.g. benzoate ester); carbonates (e.g. methoxymethylcarbonate);sulfonates (e.g. tosylate, mesylate); acyclic ketal (e.g. dimethylacetal); cyclic ketals (e.g., 1,3-dioxane or 1,3-dioxolanes); acyclicacetal; cyclic acetal; acyclic hemiacetal; cyclic hemiacetal; and cyclicdithioketals (e.g., 1,3-dithiane or 1,3-dithiolane). As used herein, any“PG” group(s) such as, without limitation, PG¹, PG² and PG³ represent aprotecting group moiety.

“Leaving group” as used herein refers to any atom or moiety that iscapable of being displaced by another atom or moiety in a chemicalreaction. More specifically, in some embodiments, “leaving group” refersto the atom or moiety that is displaced in a nucleophilic substitutionreaction. In some embodiments, “leaving groups” are any atoms ormoieties that are conjugate bases of strong acids. Examples of suitableleaving groups include, but are not limited to, tosylates and halogens.Non-limiting characteristics and examples of leaving groups can befound, for example in Organic Chemistry, 2d ed., Francis Carey (1992),pages 328-331; Introduction to Organic Chemistry, 2d ed., AndrewStreitwieser and Clayton Heathcock (1981), pages 169-171; and OrganicChemistry, 5^(th) ed., John McMurry (2000), pages 398 and 408; all ofwhich are incorporated herein by reference for the limited purpose ofdisclosing characteristics and examples of leaving groups.

The terms “pure,” “purified,” “substantially purified,” and “isolated”as used herein refer to the compound of the embodiment being free ofother, dissimilar compounds with which the compound, if found in itsnatural state, would be associated in its natural state. In certainembodiments described as “pure,” “purified,” “substantially purified,”or “isolated” herein, the compound may comprise at least 0.5%, 1%, 5%,10%, or 20%, and most preferably at least 50% or 75% of the mass, byweight, of a given sample.

The terms “derivative,” “variant,” or other similar term refers to acompound that is an analog of the other compound.

As used herein, the abbreviations for any protective groups, amino acidsand other compounds, are, unless indicated otherwise, in accord withtheir common usage, recognized abbreviations, or the IUPAC-IUBCommission on Biochemical Nomenclature (See, Biochem. 11:942-944(1972)).

It is understood that, in any compound described herein having one ormore chiral centers, if an absolute stereochemistry is not expresslyindicated, then each center may independently be of R-configuration orS-configuration or a mixture thereof. Thus, the compounds providedherein may be enantiomerically pure or be stereoisomeric mixtures. Inaddition it is understood that, in any compound described herein havingone or more double bond(s) generating geometrical isomers that can bedefined as E or Z, each double bond may independently be E or Z amixture thereof. Likewise, all tautomeric forms are also intended to beincluded.

A “prodrug” refers to an agent that is converted into the parent drug invivo. Prodrugs are often useful because, in some situations, they may beeasier to administer than the parent drug. They may, for instance, bebioavailable by oral administration whereas the parent is not. Theprodrug may also have improved solubility in pharmaceutical compositionsover the parent drug. An example, without limitation, of a prodrug wouldbe a compound which is administered as an ester (the “prodrug”) tofacilitate transmittal across a cell membrane where water solubility isdetrimental to mobility but which then is metabolically hydrolyzed tothe carboxylic acid, the active entity, once inside the cell wherewater-solubility is beneficial. A further example of a prodrug might bea short peptide (polyaminoacid) bonded to an acid group where thepeptide is metabolized to reveal the active moiety. Conventionalprocedures for the selection and preparation of suitable prodrugderivatives are described, for example, in Design of Prodrugs, (ed. H.Bundgaard, Elsevier, 1985), which is hereby incorporated herein byreference for the limited purpose describing procedures and preparationof suitable prodrug derivatives.

The term “pro-drug ester” refers to derivatives of the compoundsdisclosed herein formed by the addition of any of several ester-forminggroups that are hydrolyzed under physiological conditions. Examples ofpro-drug ester groups include pivaloyloxymethyl, acetoxymethyl,phthalidyl, indanyl and methoxymethyl, as well as other such groupsknown in the art, including a (5-R-2-oxo-1,3-dioxolen-4-yl)methyl group.Other examples of pro-drug ester groups can be found in, for example, T.Higuchi and V. Stella, in “Pro-drugs as Novel Delivery Systems”, Vol.14, A.C.S. Symposium Series, American Chemical Society (1975); and“Bioreversible Carriers in Drug Design: Theory and Application”, editedby E. B. Roche, Pergamon Press: New York, 14-21 (1987) (providingexamples of esters useful as prodrugs for compounds containing carboxylgroups). Each of the above-mentioned references is herein incorporatedby reference for the limited purpose of disclosing ester-forming groupsthat can form prodrug esters.

The term “pharmaceutically acceptable salt” refers to a salt of acompound that does not cause significant irritation to an organism towhich it is administered and does not abrogate the biological activityand properties of the compound. In some embodiments, the salt is an acidaddition salt of the compound. Pharmaceutical salts can be obtained byreacting a compound with inorganic acids such as hydrohalic acid (e.g.,hydrochloric acid or hydrobromic acid), sulfuric acid, nitric acid,phosphoric acid and the like. Pharmaceutical salts can also be obtainedby reacting a compound with an organic acid such as aliphatic oraromatic carboxylic or sulfonic acids, for example acetic, succinic,lactic, malic, tartaric, citric, ascorbic, nicotinic, methanesulfonic,ethanesulfonic, p-toluensulfonic, salicylic or naphthalenesulfonic acid.Pharmaceutical salts can also be obtained by reacting a compound with abase to form a salt such as an ammonium salt, an alkali metal salt, suchas a sodium or a potassium salt, an alkaline earth metal salt, such as acalcium or a magnesium salt, a salt of organic bases such asdicyclohexylamine, N-methyl-D-glucamine, tris(hydroxymethyl)methylamine,C₁-C₇ alkylamine, cyclohexylamine, triethanolamine, ethylenediamine, andsalts with amino acids such as arginine, lysine, and the like.

Compounds

Some embodiments disclosed herein relate to a compound of Formula (I),or pharmaceutically acceptable salt, ester or prodrug thereof:

wherein: R¹ can have a structure selected from:

wherein R⁴ can be selected from a mono-substituted, a poly-substitutedor an unsubstituted variant of the following residues: aryl, aryl(C₁₋₆alkyl), heteroaryl, heteroaryl(C₁₋₆ alkyl), heterocyclyl andheterocyclyl(C₁₋₆ alkyl), wherein R⁴ can be optionally substituted with

wherein A can be selected from a mono-substituted, a poly-substituted oran unsubstituted variant of the following residues: heterocyclyl, aryland heteroaryl; and Z¹ can be selected from O (oxygen), S (sulfur), N═N,O(CH₂)₁₋₆, S(O)₂N(R¹⁷), S(O)₂N(R¹⁷)(CH₂)₁₋₆, C(═O)N(R¹⁷), N(R¹⁷)C(═O),N(R¹⁷)C(═O)(CH₂)₁₋₆, N(R¹⁷)C(═O)O(CH₂)₁₋₆, S(O)₂, C(═O), (CH₂)₁₋₆C(═O),O(CH₂)₁₋₆C(═O), (CH₂)₁₋₆ N(R¹⁷)C(═O), CH═CH—C(═O)N(R¹⁷), CH═CH—C(═O),O(CH₂)₁₋₆O, O(CH₂)₁₋₆ and N(R^(17a))C(═O)N(R^(17b)), wherein R¹⁷,R^(17a) and R^(17b) can be independently selected from: H, C₁₋₄ alkyl, asubstituted or unsubstituted benzyl, an allyl, and t-butoxycarbonyl(t-BOC); R² can be selected from a hydrogen, a halogen, cyano, amono-substituted, a poly-substituted or an unsubstituted variant of thefollowing residues: C₁-C₁₂ alkyl, C₂-C₁₂ alkenyl, C₂-C₁₂ alkynyl, C₃-C₁₂cycloalkyl, C₃-C₁₂ cycloalkenyl, C₃-C₁₂ cycloalkynyl, C₃-C₁₂heterocyclyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl,(cycloalkyl)alkyl, (heterocyclyl)alkyl, acyl, acylalkyl,alkyloxycarbonyloxy, carbonylacyl, aminocarbonyl, azido, azidoalkyl,mono-haloalkyl, di-haloakyl, tri-haloalkyl, aminoalkyl, salt of anaminoalkyl, carboxyalkyl, a salt of a carboxyalkyl, alkylamino, a saltof an alkylamino, dialkylamino, a salt of a dialkylamino, alkylthio,arylthio, carboxy, alkoxysulfinyl, thiocyano, boronic acidalkyl, boronicesteralkyl, sulfoalkyl, a salt of a sulfoalkyl, alkoxysulfonylalkyl,sulfooxyalkyl, a salt of a sulfooxyalkyl, alkoxysulfonyloxyalkyl,phosphonooxyalkyl, a salt of a phosphonooxyalkyl,(alkylphosphooxy)alkyl, phosphorylalkyl, a salt of a phosphorylalkyl,(alkylphosphoryl)alkyl, pyridinylalkyl, a salt of a pyridinylalkyl, asalt of a heteroarylalkyl guanidino, a salt of a guanidino, andguanidinoalkyl; R³ can be selected from hydrogen, halogen, amono-substituted, a poly-substituted or an unsubstituted variant of thefollowing residues: C₁₋₆ alkyl, C₃₋₆ cycloalkyl, C₂₋₆ alkenyl, C₃₋₆cycloalkenyl, aryl, and arylalkyl; n can be 1, 2 or 3; E¹, E³, E⁴ and E⁵can be each independently a substituted or unsubstituted heteroatom; E²can be a substituted or unsubstituted heteroatom (such as NH) or —CH₂—group; and provided that when R¹ is

R⁴ has a molecular weight equal to or greater than 92 g/mol; andprovided that when R¹ is

R⁴ has a molecular weight equal to or greater than 77 g/mol.

In some embodiments, when R¹ is

R⁴ has a molecular weight equal to or greater than 107 g/mol. In otherembodiments, when R¹ is

R⁴ has a molecular weight equal to or greater than 92 g/mol. In anembodiment, when R¹ is

R⁴ has a molecular weight equal to or greater than 122 g/mol. In anotherembodiment, when R¹ is

R⁴ has a molecular weight equal to or greater than 107 g/mol.

In some embodiments, R¹ can have a structure selected from:

wherein: R^(5a), R^(5b), R^(5c), R^(5d), R^(5e), R^(9a), R^(9b), R^(9c),R^(9d), R^(9e), R^(13a), R^(13b), R^(13c), R^(13d) and R^(13e) can beeach independently selected from: hydrogen, halo, nitro, cyano, amono-substituted, a poly-substituted or an unsubstituted variant of thefollowing residues: C₁₋₂₄ alkyl, C₂₋₂₄ alkenyl, C₂₋₂₄ alkynyl,mono-haloalkyl, di-haloalkyl, tri-haloalkyl, mono-haloalkoxy,di-haloalkoxy, tri-haloalkoxy, cycloalkyl, cycloalkenyl, cycloalkynyl,aryl, heteroaryl, heterocyclyl, amino, mono-substituted amine,di-substituted amine, alkoxy, acyl, aminoalkyl, salt of an aminoalkyl,carboxyalkyl, a salt of a carboxyalkyl, alkylamino, a salt of analkylamino, dialkylamino, a salt of a dialkylamino, alkylthio, arylthio,carboxy, alkoxysulfinyl, thiocyano, boronic acidalkyl, boronicesteralkyl, sulfoalkyl, a salt of a sulfoalkyl, alkoxysulfonylalkyl,sulfooxyalkyl, a salt of a sulfooxyalkyl, alkoxysulfonyloxyalkyl,phosphonooxyalkyl, a salt of a phosphonooxyalkyl,(alkylphosphooxy)alkyl, phosphorylalkyl, a salt of a phosphorylalkyl,(alkylphosphoryl)alkyl, pyridinylalkyl, a salt of a pyridinylalkyl, asalt of a heteroarylalkyl guanidino, a salt of a guanidino, andguanidinoalkyl; R^(6a), R^(6b), R^(6c), R^(10a), R^(10b), R^(10c),R^(14a), R^(14b) and R^(14c) can be each independently selected from:hydrogen, halo, nitro, cyano, a mono-substituted, a poly-substituted oran unsubstituted variant of the following residues: C₁₋₂₄ alkyl, C₂₋₂₄alkenyl, C₂₋₂₄ alkynyl, mono-haloalkyl, di-haloalkyl, tri-haloalkyl,mono-haloalkoxy, di-haloalkoxy, tri-haloalkoxy, amino, mono-substitutedamine, di-substituted amine, alkoxy, acyl, aminoalkyl, salt of anaminoalkyl, carboxyalkyl, a salt of a carboxyalkyl, alkylamino, a saltof an alkylamino, dialkylamino, a salt of a dialkylamino, alkylthio,arylthio, carboxy, alkoxysulfinyl, thiocyano, boronic acidalkyl, boronicesteralkyl, sulfoalkyl, a salt of a sulfoalkyl, alkoxysulfonylalkyl,sulfooxyalkyl, a salt of a sulfooxyalkyl, alkoxysulfonyloxyalkyl,phosphonooxyalkyl, a salt of a phosphonooxyalkyl,(alkylphosphooxy)alkyl, phosphorylalkyl, a salt of a phosphorylalkyl,(alkylphosphoryl)alkyl, pyridinylalkyl, a salt of a pyridinylalkyl, asalt of a heteroarylalkyl guanidino, a salt of a guanidino, andguanidinoalkyl; R^(7a), R^(7b), R^(7c), R^(11a), R^(11b), R^(11c),R^(15a), R^(15b) and R^(15c) can be each independently selected from:hydrogen, halo, a mono-substituted, a poly-substituted or anunsubstituted variant of the following residues: C₁₋₂₄ alkyl, C₂₋₂₄alkenyl, C₂₋₂₄ alkynyl, nitro, mono-haloalkyl, di-haloalkyl,tri-haloalkyl, mono-haloalkoxy, di-haloalkoxy, tri-haloalkoxy, amino,mono-substituted amine, di-substituted amine, alkoxy, acyl, aminoalkyl,salt of an aminoalkyl, carboxyalkyl, a salt of a carboxyalkyl,alkylamino, a salt of an alkylamino, dialkylamino, a salt of adialkylamino, alkylthio, arylthio, carboxy, cyano, alkoxysulfinyl,thiocyano, boronic acidalkyl, boronic esteralkyl, sulfoalkyl, a salt ofa sulfoalkyl, alkoxysulfonylalkyl, sulfooxyalkyl, a salt of asulfooxyalkyl, alkoxysulfonyloxyalkyl, phosphonooxyalkyl, a salt of aphosphonooxyalkyl, (alkylphosphooxy)alkyl, phosphorylalkyl, a salt of aphosphorylalkyl, (alkylphosphoryl)alkyl, pyridinylalkyl, a salt of apyridinylalkyl, a salt of a heteroarylalkyl guanidino, a salt of aguanidino, and guanidinoalkyl; R^(8a), R^(8b), R^(8c), R^(8d), R^(12a),R^(12b), R^(12c), R^(12d), R^(16a), R^(16b), R^(16c) and R^(16d) can beeach independently selected from: hydrogen, halo, nitro, cyano, amono-substituted, a poly-substituted or an unsubstituted variant of thefollowing residues: C₁₋₂₄ alkyl, C₂₋₂₄ alkenyl, C₂₋₂₄ alkynyl,mono-haloalkyl, di-haloalkyl, tri-haloalkyl, mono-haloalkoxy,di-haloalkoxy, tri-haloalkoxy, amino, mono-substituted amine,di-substituted amine, alkoxy, acyl, aminoalkyl, salt of an aminoalkyl,carboxyalkyl, a salt of a carboxyalkyl, alkylamino, a salt of analkylamino, dialkylamino, a salt of a dialkylamino, alkylthio, arylthio,carboxy, alkoxysulfinyl, thiocyano, boronic acidalkyl, boronicesteralkyl, sulfoalkyl, a salt of a sulfoalkyl, alkoxysulfonylalkyl,sulfooxyalkyl, a salt of a sulfooxyalkyl, alkoxysulfonyloxyalkyl,phosphonooxyalkyl, a salt of a phosphonooxyalkyl,(alkylphosphooxy)alkyl, phosphorylalkyl, a salt of a phosphorylalkyl,(alkylphosphoryl)alkyl, pyridinylalkyl, a salt of a pyridinylalkyl, asalt of a heteroarylalkyl guanidino, a salt of a guanidino, andguanidinoalkyl and —S(═O)₂O⁻; B, D and F can be each independentlyselected from: a mono-substituted, a poly-substituted or anunsubstituted variant of the following residues: heterocyclyl, aryl,heteroaryl, cycloalkyl and cycloalkenyl; C, E and G can be eachindependently selected from: a mono-substituted, a poly-substituted oran unsubstituted variant of the following residues: heterocyclyl, aryl,heteroaryl, cycloalkyl and cycloalkenyl; A can be selected from: amono-substituted, a poly-substituted or an unsubstituted variant of thefollowing residues: heterocyclyl, aryl, heteroaryl, cycloalkyl andcycloalkenyl; and Z¹ can be selected from: O, S, N═N, O(CH₂)₁₋₆,S(O)₂N(R¹⁷), S(O)₂N(R¹⁷)(CH₂)₁₋₆, C(═O)N(R¹⁷), N(R¹⁷)C(═O),N(R¹⁷)C(═O)(CH₂)₁₋₆, N(R¹⁷)C(═O)O(CH₂)₁₋₆, S(O)₂, C(═O), (CH₂)₁₋₆C(═O),O(CH₂)₁₋₆C(═O), (CH₂)₁₋₆ N(R¹⁷)C(═O), CH═CH—C(═O)N(R¹⁷), CH═CH—C(═O),O(CH₂)₁₋₆O, O(CH₂)₁₋₆ and N(R^(17a))C(═O)N(R^(17b)), wherein R¹⁷,R^(17a) and R^(17b) are independently selected from: H, C₁₋₄ alkyl, asubstituted or unsubstituted benzyl, an allyl, and t-butoxycarbonyl(t-BOC).

In some embodiments, R¹ can have the structure:

wherein: R^(5a), R^(5b), R^(5c), R^(5d), and R^(5e) can be eachindependently selected from: hydrogen, halo, nitro, cyano, amono-substituted, a poly-substituted or an unsubstituted variant of thefollowing residues: C₁₋₂₄ alkyl, C₂₋₂₄ alkenyl, C₂₋₂₄ alkynyl,mono-haloalkyl, di-haloalkyl, tri-haloalkyl, mono-haloalkoxy,di-haloalkoxy, tri-haloalkoxy, cycloalkyl, cycloalkenyl, cycloalkynyl,aryl, heteroaryl, heterocyclyl, amino, mono-substituted amine,di-substituted amine, alkoxy, acyl, aminoalkyl, salt of an aminoalkyl,carboxyalkyl, a salt of a carboxyalkyl, alkylamino, a salt of analkylamino, dialkylamino, a salt of a dialkylamino, alkylthio, arylthio,carboxy, alkoxysulfinyl, thiocyano, boronic acidalkyl, boronicesteralkyl, sulfoalkyl, a salt of a sulfoalkyl, alkoxysulfonylalkyl,sulfooxyalkyl, a salt of a sulfooxyalkyl, alkoxysulfonyloxyalkyl,phosphonooxyalkyl, a salt of a phosphonooxyalkyl,(alkylphosphooxy)alkyl, phosphorylalkyl, a salt of a phosphorylalkyl,(alkylphosphoryl)alkyl, pyridinylalkyl, a salt of a pyridinylalkyl, asalt of a heteroarylalkyl guanidino, a salt of a guanidino, andguanidinoalkyl.

In some embodiments, R^(5a), R^(5b), R^(5c), R^(5d), and R^(5e) can beeach independently selected from: hydrogen, halo, nitro, amono-substituted, a poly-substituted or an unsubstituted variant of thefollowing residues: C₁₋₂₄ alkyl, cycloalkyl, cycloalkenyl, aryl,heteroaryl, heterocyclyl, mono-haloalkyl, di-haloalkyl, tri-haloalkyl,mono-haloalkoxy, di-haloalkoxy, tri-haloalkoxy, amino, mono-substitutedamine, di-substituted amine, alkoxy, and carboxy. In another embodiment,R^(5a), R^(5b), R^(5c), R^(5d), and R^(5e) are each independentlyselected from: hydrogen, halo, nitro, a mono-substituted, apoly-substituted or an unsubstituted C₁₋₂₄ alkyl, aryl, tri-haloalkyl,tri-haloalkoxy, mono-substituted amine, a mono-substituted, apoly-substituted or an unsubstituted alkoxy, and a mono-substituted, apoly-substituted or an unsubstituted carboxy.

In some embodiments, when R¹ has the structure:

the phenyl ring of R¹ can be an unsubstituted phenyl ring, anortho-substituted phenyl ring, a meta-substituted phenyl ring or apara-substituted phenyl ring. In some embodiments, at least one ofR^(5a), R^(5b), R^(5c), R^(5d), and R^(5e) is not hydrogen. In otherembodiments, at least two of R^(5a), R^(5b), R^(5c), R^(5d), and R^(5e)are not hydrogen. In still other embodiments, at least three of R^(5a),R^(5b), R^(5c), R^(5d), and R^(5e) are not hydrogen. In yet sill otherembodiments, at least four of R^(5a), R^(5b), R^(5c), R^(5d), and R^(5e)are not hydrogen. In an embodiment, R^(5c) is not hydrogen. For example,when R^(5c) is not hydrogen, R^(5c) can be selected from halogen, nitro,trihaloalkyl (e.g., CF₃), trihaloalkoxy (e.g., OCF₃), acyl (e.g.,C(═O)OH) and C₁₋₆ alkyl. In some embodiments, at least one of R^(5b) orR^(5d) is not hydrogen. As an example, at least one of R^(5b) or R^(5d)can be an acyl group, such as C(═O)OH. In other embodiments, R^(5c) isnot hydrogen and at least one of R^(5b) or R^(5d) is not hydrogen. Thus,the phenyl ring is a para- and meta-substituted phenyl ring. In anembodiment, R^(5b) or R^(5d) can be a nitro group and R^(5c) can be amono-substituted amine. In other embodiments, R^(5c) is not hydrogen andat least one of R^(5a) or R^(5e) is not hydrogen. Accordingly, thephenyl ring is a para- and ortho-substituted phenyl ring. As example,R^(5c) can be a C₁₋₆ alkyl group and one or both of R^(5a) and R^(5e)can also be a C₁₋₆ alkyl group.

A non-limiting list of R¹ include the following:

In some embodiments, R¹ can have the structure:

wherein: R^(6a), R^(6b) and R^(6c) can be each independently selectedfrom: hydrogen, halo, nitro, cyano, a mono-substituted, apoly-substituted or an unsubstituted variant of the following residues:C₁₋₂₄ alkyl, C₂₋₂₄ alkenyl, C₂₋₂₄ alkynyl, mono-haloalkyl, di-haloalkyl,tri-haloalkyl, mono-haloalkoxy, di-haloalkoxy, tri-haloalkoxy, amino,mono-substituted amine, di-substituted amine, alkoxy, acyl, aminoalkyl,salt of an aminoalkyl, carboxyalkyl, a salt of a carboxyalkyl,alkylamino, a salt of an alkylamino, dialkylamino, a salt of adialkylamino, alkylthio, arylthio, carboxy, alkoxysulfinyl, thiocyano,boronic acidalkyl, boronic esteralkyl, sulfoalkyl, a salt of asulfoalkyl, alkoxysulfonylalkyl, sulfooxyalkyl, a salt of asulfooxyalkyl, alkoxysulfonyloxyalkyl, phosphonooxyalkyl, a salt of aphosphonooxyalkyl, (alkylphosphooxy)alkyl, phosphorylalkyl, a salt of aphosphorylalkyl, (alkylphosphoryl)alkyl, pyridinylalkyl, a salt of apyridinylalkyl, a salt of a heteroarylalkyl guanidino, a salt of aguanidino, and guanidinoalkyl; and B can be selected from: amono-substituted, a poly-substituted or an unsubstituted variant of thefollowing residues: heterocyclyl, aryl, heteroaryl, cycloalkyl andcycloalkenyl.

In an embodiment, B can be a mono-substituted, a poly-substituted or anunsubstituted aryl ring. For example, B can be a mono-substituted, apoly-substituted or an unsubstituted phenyl. In some embodiments, B canbe a mono-substituted phenyl. In other embodiments, B can be anunsubstituted phenyl. In another embodiment, B can be amono-substituted, a poly-substituted or an unsubstituted heteroarylring. In still another embodiment, B can be a mono-substituted, apoly-substituted or an unsubstituted heterocyclyl ring. In yet stillother embodiments, B can be a mono-substituted, a poly-substituted or anunsubstituted cycloalkyl ring. In some embodiments, B can be amono-substituted, a poly-substituted or an unsubstituted cycloalkenylring. In some embodiments, R^(6a), R^(6b) and R^(6c) can be eachhydrogen. In an embodiment, R^(6a), R^(6b) and R^(6c) can be eachhydrogen and B can be a mono-substituted, a poly-substituted or anunsubstituted phenyl ring. In some embodiments, B can be a substitutedphenyl ring substituted with amino, mono-substituted amino, ordi-substituted amino.

Examples of R¹ include the following:

In some embodiments, R¹ can have the structure:

wherein: R^(7a), R^(7b) and R^(7c) can be each independently selectedfrom: hydrogen, halo, nitro, cyano, a mono-substituted, apoly-substituted or an unsubstituted variant of the following residues:C₁₋₂₄ alkyl, C₂₋₂₄ alkenyl, C₂₋₂₄ alkynyl, mono-haloalkyl, di-haloalkyl,tri-haloalkyl, mono-haloalkoxy, di-haloalkoxy, tri-haloalkoxy, amino,mono-substituted amine, di-substituted amine, alkoxy, acyl, aminoalkyl,salt of an aminoalkyl, carboxyalkyl, a salt of a carboxyalkyl,alkylamino, a salt of an alkylamino, dialkylamino, a salt of adialkylamino, alkylthio, arylthio, carboxy, alkoxysulfinyl, thiocyano,boronic acidalkyl, boronic esteralkyl, sulfoalkyl, a salt of asulfoalkyl, alkoxysulfonylalkyl, sulfooxyalkyl, a salt of asulfooxyalkyl, alkoxysulfonyloxyalkyl, phosphonooxyalkyl, a salt of aphosphonooxyalkyl, (alkylphosphooxy)alkyl, phosphorylalkyl, a salt of aphosphorylalkyl, (alkylphosphoryl)alkyl, pyridinylalkyl, a salt of apyridinylalkyl, a salt of a heteroarylalkyl guanidino, a salt of aguanidine and guanidinoalkyl; and C can be selected from: amono-substituted, a poly-substituted or an unsubstituted variant of thefollowing residues: heterocyclyl, aryl, heteroaryl, cycloalkyl andcycloalkenyl.

In some embodiments, C can be a mono-substituted, a poly-substituted oran unsubstituted heterocyclyl ring. In an embodiment, C can be apoly-substituted heterocyclyl ring. In some embodiments, including thoseof this paragraph, R^(7a), R^(7b) and R^(7c) can each be a C₁₋₂₄ alkyl(for example, C₁₋₆ alkyl such as methyl). In other embodiments,including those of this paragraph, R^(7a), R^(7b) and R^(7c) can each behydrogen.

An example of R¹ with the structure

In other embodiments, C can be a mono-substituted, a poly-substituted oran unsubstituted aryl ring, such as a mono-substituted, apoly-substituted or an unsubstituted phenyl. In an embodiment, C can bean unsubstituted phenyl. In still other embodiments, C can be amono-substituted, a poly-substituted or an unsubstituted heteroarylring. In yet still other embodiments, C can be a mono-substituted, apoly-substituted or an unsubstituted cycloalkyl ring. In someembodiments, C can be a mono-substituted, a poly-substituted or anunsubstituted cycloalkenyl ring. In some embodiments, including those ofthis paragraph, R^(7a), R^(7b) and R^(7c) can be each hydrogen. As anexample, when C is a mono-substituted, a poly-substituted or anunsubstituted aryl ring, R^(7a), R^(7b) and R^(7c) can be each hydrogen.

An example of R¹ of with the structure

In some embodiments, R¹ can have the structure:

wherein: R^(8a), R^(8b), R^(8c) and R^(8d) can be each independentlyselected from: hydrogen, halo, nitro, cyano, a mono-substituted, apoly-substituted or an unsubstituted variant of the following residues:C₁₋₂₄ alkyl, C₂₋₂₄ alkenyl, C₂₋₂₄ alkynyl, mono-haloalkyl, di-haloalkyl,tri-haloalkyl, mono-haloalkoxy, di-haloalkoxy, tri-haloalkoxy, amino,mono-substituted amine, di-substituted amine, alkoxy, acyl, aminoalkyl,salt of an aminoalkyl, carboxyalkyl, a salt of a carboxyalkyl,alkylamino, a salt of an alkylamino, dialkylamino, a salt of adialkylamino, alkylthio, arylthio, carboxy, alkoxysulfinyl, thiocyano,boronic acidalkyl, boronic esteralkyl, sulfoalkyl, a salt of asulfoalkyl, alkoxysulfonylalkyl, sulfooxyalkyl, a salt of asulfooxyalkyl, alkoxysulfonyloxyalkyl, phosphonooxyalkyl, a salt of aphosphonooxyalkyl, (alkylphosphooxy)alkyl, phosphorylalkyl, a salt of aphosphorylalkyl, (alkylphosphoryl)alkyl, pyridinylalkyl, a salt of apyridinylalkyl, a salt of a heteroarylalkyl guanidino, a salt of aguanidino, guanidinoalkyl and —S(═O)₂O⁻; A can be selected from: amono-substituted, a poly-substituted or an unsubstituted variant of thefollowing residues: heterocyclyl, aryl, heteroaryl, cycloalkyl andcycloalkenyl; and Z¹ can be selected from: O, S, N═N, O(CH₂)₁₋₆,S(O)₂N(R¹⁷), S(O)₂N(R¹⁷)(CH₂)₁₋₆, C(═O)N(R¹⁷), N(R¹⁷)C(═O),N(R¹⁷)C(═O)(CH₂)₁₋₆, N(R¹⁷)C(═O)O(CH₂)₁₋₆, S(O)₂, C(═O), (CH₂)₁₋₆C(═O),O(CH₂)₁₋₆C(═O), (CH₂)₁₋₆ N(R¹⁷)C(═O), CH═CH—C(═O)N(R¹⁷), CH═CH—C(═O),O(CH₂)₁₋₆O, O(CH₂)₁₋₆ and N(R^(17a))C(═O)N(R^(17b)), wherein R¹⁷,R^(17a) and R^(17b) are independently selected from: H, C₁₋₄ alkyl, asubstituted or unsubstituted benzyl, an allyl, and t-butoxycarbonyl(t-BOC). In an embodiment, R¹⁷, R^(17a) and R^(17b) can be independentlyH or C₁₋₄ alkyl.

When R¹ is

in some embodiments, A can be a mono-substituted, a poly-substituted oran unsubstituted aryl ring. For example, A can be a mono-substituted, apoly-substituted or an unsubstituted phenyl. In an embodiment, A can bean unsubstituted phenyl ring. In another embodiment, A can be amono-substituted phenyl ring. In other embodiments, A can be amono-substituted, a poly-substituted or an unsubstituted heteroarylring. In an embodiment, A can be an unsubstituted heteroaryl ring. Inanother embodiment, A can be a poly-substituted heteroaryl ring. Instill other embodiments, A can be a mono-substituted, a poly-substitutedor an unsubstituted heterocyclyl ring. In yet still other embodiments, Acan be a mono-substituted, a poly-substituted or an unsubstitutedcycloalkyl ring. In some embodiments, A can be a mono-substituted, apoly-substituted or an unsubstituted cycloalkenyl ring.

In some embodiments, Z¹ can be O (oxygen). In other embodiments, Z¹ canbe N═N.

Examples of R¹ can have the structure:

include, but are not limited to, the following:

In any of the embodiments described with respect to R¹ having thestructure:

R^(8a), R^(8b), R^(8c) and R^(8d) can be each hydrogen.

In some embodiments, R¹ can have the structure:

wherein: R^(9a), R^(9b), R^(9c), R^(9d) and R^(9e) can be eachindependently selected from: hydrogen, halo, nitro, cyano, amono-substituted, a poly-substituted or an unsubstituted variant of thefollowing residues: C₁₋₂₄ alkyl, C₂₋₂₄ alkenyl, C₂₋₂₄ alkynyl,mono-haloalkyl, di-haloalkyl, tri-haloalkyl, mono-haloalkoxy,di-haloalkoxy, tri-haloalkoxy, cycloalkyl, cycloalkenyl, cycloalkynyl,aryl, heteroaryl, heterocyclyl, amino, mono-substituted amine,di-substituted amine, alkoxy, acyl, aminoalkyl, salt of an aminoalkyl,carboxyalkyl, a salt of a carboxyalkyl, alkylamino, a salt of analkylamino, dialkylamino, a salt of a dialkylamino, alkylthio, arylthio,carboxy, alkoxysulfinyl, thiocyano, boronic acidalkyl, boronicesteralkyl, sulfoalkyl, a salt of a sulfoalkyl, alkoxysulfonylalkyl,sulfooxyalkyl, a salt of a sulfooxyalkyl, alkoxysulfonyloxyalkyl,phosphonooxyalkyl, a salt of a phosphonooxyalkyl,(alkylphosphooxy)alkyl, phosphorylalkyl, a salt of a phosphorylalkyl,(alkylphosphoryl)alkyl, pyridinylalkyl, a salt of a pyridinylalkyl, asalt of a heteroarylalkyl guanidino, a salt of a guanidino, andguanidinoalkyl.

In some embodiments, R^(9a), R^(9b), R^(9c), R^(9d), and R^(9e) can beeach independently selected from: hydrogen, halo, nitro, cyano, amono-substituted, a poly-substituted or an unsubstituted variant of thefollowing residues: C₁₋₂₄ alkyl, cycloalkyl, cycloalkenyl, aryl,heteroaryl, heterocyclyl, mono-haloalkyl, di-haloalkyl, tri-haloalkyl,mono-haloalkoxy, di-haloalkoxy, tri-haloalkoxy, amino, mono-substitutedamine, di-substituted amine, alkoxy, and hydroxy. In other embodiments,R^(9a), R^(9b), R^(9c), R^(9d), and R^(9e) can be each independentlyselected from: hydrogen, halo, cyano, a mono-substituted, apoly-substituted or an unsubstituted C₁₋₂₄ alkyl, a mono-substituted, apoly-substituted or an unsubstituted aryl, amino, tri-haloalkyl, amono-substituted, a poly-substituted or an unsubstituted alkoxy andhydroxy.

In some embodiments, when R¹ has the structure:

the phenyl ring of R¹ can be an unsubstituted phenyl ring, anortho-substituted phenyl ring, a meta-substituted phenyl ring or apara-substituted phenyl ring. In some embodiments, at least one ofR^(9a), R^(9b), R^(9c), R^(9d), and R^(9e) is not hydrogen. In otherembodiments, at least two of R^(9a), R^(9b), R^(9c), R^(9d), and R^(9e)are not hydrogen. In still other embodiments, at least three of R^(9a),R^(9b), R^(9c), R^(9d), and R^(9e) are not hydrogen. In yet sill otherembodiments, at least four of R^(9a), R^(9b), R^(9c), R^(9d), and R^(9e)are not hydrogen. In an embodiment, R^(9c) is not hydrogen. For example,when R^(9c) is not hydrogen, R^(9c) can be selected from halogen,alkoxy, trihalolalkyl (for example, CF₃), cyano, C₁₋₈ alkyl, amino,hydroxy, and aryl. In an embodiment, when R^(9c) is an aryl ring, thearyl ring can be an optionally substituted phenyl ring. In anotherembodiment, when R^(9c) is an aryl ring, the aryl ring can be anunsubstituted phenyl ring. In some embodiments, at least one of R^(9b)or R^(9d) is not hydrogen. As an example, at least one of R^(9b) orR^(9d) can be a halogen. In other embodiments, R^(9c) is not hydrogenand at least one of R^(9b) or R^(9d) is not hydrogen. Thus, the phenylring is a para- and meta-substituted phenyl ring. In some embodiments,R^(9c) is not hydrogen and at least one of R^(9a) or R^(9e) is nothydrogen. Accordingly, the phenyl ring is a para- and ortho-substitutedphenyl ring. As example, R^(9c) can be a C₁₋₈ alkyl group and one orboth of R^(9a) and R^(9e) can also be a C₁₋₈ alkyl group.

Examples of R¹ having the structure

include, but are not limited to, the following:

In some embodiments, R¹ can have the structure:

wherein: R^(10a), R^(10b) and R^(10c) can be each independently selectedfrom: hydrogen, halo, nitro, cyano, a mono-substituted, apoly-substituted or an unsubstituted variant of the following residues:C₁₋₂₄ alkyl, C₂₋₂₄ alkenyl, C₂₋₂₄ alkynyl, mono-haloalkyl, di-haloalkyl,tri-haloalkyl, mono-haloalkoxy, di-haloalkoxy, tri-haloalkoxy, amino,mono-substituted amine, di-substituted amine, alkoxy, acyl, aminoalkyl,salt of an aminoalkyl, carboxyalkyl, a salt of a carboxyalkyl,alkylamino, a salt of an alkylamino, dialkylamino, a salt of adialkylamino, alkylthio, arylthio, carboxy, alkoxysulfinyl, thiocyano,boronic acidalkyl, boronic esteralkyl, sulfoalkyl, a salt of asulfoalkyl, alkoxysulfonylalkyl, sulfooxyalkyl, a salt of asulfooxyalkyl, alkoxysulfonyloxyalkyl, phosphonooxyalkyl, a salt of aphosphonooxyalkyl, (alkylphosphooxy)alkyl, phosphorylalkyl, a salt of aphosphorylalkyl, (alkylphosphoryl)alkyl, pyridinylalkyl, a salt of apyridinylalkyl, a salt of a heteroarylalkyl guanidino, a salt of aguanidino, and guanidinoalkyl; and D can be selected from: amono-substituted, a poly-substituted or an unsubstituted variant of thefollowing residues: heterocyclyl, aryl, heteroaryl, cycloalkyl andcycloalkenyl.

In some embodiments, D can be a mono-substituted, a poly-substituted oran unsubstituted aryl ring, such as a mono-substituted, apoly-substituted or an unsubstituted phenyl. In an embodiment, D can bea mono-substituted phenyl. In another embodiment, D can be anunsubstituted phenyl. In other embodiments, D can be a mono-substituted,a poly-substituted or an unsubstituted heteroaryl ring. In still otherembodiments, D can be a mono-substituted, a poly-substituted or anunsubstituted heterocyclyl ring. In yet still other embodiments, D canbe a mono-substituted, a poly-substituted or an unsubstituted cycloalkylring. In some embodiments, D can be a mono-substituted, apoly-substituted or an unsubstituted cycloalkenyl ring. In someembodiments, including those of this paragraph, R^(10a), R^(10b) andR^(10c) can be each hydrogen.

An example of R¹ is:

In some embodiments, R¹ can have the structure:

wherein: R^(11a), R^(11b) and R^(11c) can be each independently selectedfrom: hydrogen, halo, nitro, cyano, a mono-substituted, apoly-substituted or an unsubstituted variant of the following residues:C₁₋₂₄ alkyl, C₂₋₂₄ alkenyl, C₂₋₂₄ alkynyl, mono-haloalkyl, di-haloalkyl,tri-haloalkyl, mono-haloalkoxy, di-haloalkoxy, tri-haloalkoxy, amino,mono-substituted amine, di-substituted amine, alkoxy, acyl, aminoalkyl,salt of an aminoalkyl, carboxyalkyl, a salt of a carboxyalkyl,alkylamino, a salt of an alkylamino, dialkylamino, a salt of adialkylamino, alkylthio, arylthio, carboxy, alkoxysulfinyl, thiocyano,boronic acidalkyl, boronic esteralkyl, sulfoalkyl, a salt of asulfoalkyl, alkoxysulfonylalkyl, sulfooxyalkyl, a salt of asulfooxyalkyl, alkoxysulfonyloxyalkyl, phosphonooxyalkyl, a salt of aphosphonooxyalkyl, (alkylphosphooxy)alkyl, phosphorylalkyl, a salt of aphosphorylalkyl, (alkylphosphoryl)alkyl, pyridinylalkyl, a salt of apyridinylalkyl, a salt of a heteroarylalkyl guanidino, a salt of aguanidino, and guanidinoalkyl; and E can be selected from: amono-substituted, a poly-substituted or an unsubstituted variant of thefollowing residues: heterocyclyl, aryl, heteroaryl, cycloalkyl andcycloalkenyl.

In some embodiments, E can be a mono-substituted, a poly-substituted oran unsubstituted heteroaryl ring. In an embodiment, E can be apoly-substituted heteroaryl ring. In some embodiments, E can be amono-substituted, a poly-substituted or an unsubstituted aryl ring. Inan embodiment, E can be a mono-substituted, a poly-substituted or anunsubstituted phenyl ring. In still other embodiments, E can be amono-substituted, a poly-substituted or an unsubstituted heterocyclylring. In yet still other embodiments, E can be a mono-substituted, apoly-substituted or an unsubstituted cycloalkyl ring. In someembodiments, E can be a mono-substituted, a poly-substituted or anunsubstituted cycloalkenyl ring. In some embodiments, including thosedescribed in the present paragraph, R^(11a), R^(11b) and R^(11c) can beeach hydrogen. In other embodiments, R^(11a), R^(11b) and R^(11c) can beeach C₁₋₄ alkyl.

A non-limiting list of examples where R¹ is

are:

In some embodiments, R¹ can have the structure:

wherein: R^(12a), R^(12b), R^(12c) and R^(12d) can be each independentlyselected from: hydrogen, halo, nitro, cyano, a mono-substituted, apoly-substituted or an unsubstituted variant of the following residues:C₁₋₂₄ alkyl, C₂₋₂₄ alkenyl, C₂₋₂₄ alkynyl, mono-haloalkyl, di-haloalkyl,tri-haloalkyl, mono-haloalkoxy, di-haloalkoxy, tri-haloalkoxy, amino,mono-substituted amine, di-substituted amine, alkoxy, acyl, aminoalkyl,salt of an aminoalkyl, carboxyalkyl, a salt of a carboxyalkyl,alkylamino, a salt of an alkylamino, dialkylamino, a salt of adialkylamino, alkylthio, arylthio, carboxy, alkoxysulfinyl, thiocyano,boronic acidalkyl, boronic esteralkyl, sulfoalkyl, a salt of asulfoalkyl, alkoxysulfonylalkyl, sulfooxyalkyl, a salt of asulfooxyalkyl, alkoxysulfonyloxyalkyl, phosphonooxyalkyl, a salt of aphosphonooxyalkyl, (alkylphosphooxy)alkyl, phosphorylalkyl, a salt of aphosphorylalkyl, (alkylphosphoryl)alkyl, pyridinylalkyl, a salt of apyridinylalkyl, a salt of a heteroarylalkyl guanidino, a salt of aguanidino, guanidinoalkyl and —S(═O)₂O⁻; A can be selected from: amono-substituted, a poly-substituted or an unsubstituted variant of thefollowing residues: heterocyclyl, aryl, heteroaryl, cycloalkyl andcycloalkenyl; and Z¹ can be selected from: O, S, N═N, O(CH₂)₁₋₆,S(O)₂N(R¹⁷), S(O)₂N(R¹⁷)(CH₂)₁₋₆, C(═O)N(R¹⁷), N(R¹⁷)C(═O),N(R¹⁷)C(═O)(CH₂)₁₋₆, N(R¹⁷)C(═O)O(CH₂)₁₋₆, S(O)₂, C(═O), (CH₂)₁₋₆C(═O),O(CH₂)₁₋₆C(═O), (CH₂)₁₋₆ N(R¹⁷)C(═O), CH═CH—C(═O)N(R¹⁷), CH═CH—C(═O),O(CH₂)₁₋₆O, O(CH₂)₁₋₆ and N(R^(17a)) C(═O)N(R^(17b)), wherein R¹⁷,R^(17a) and R^(17b) are independently selected from: H, C₁₋₄ alkyl, asubstituted or unsubstituted benzyl, an allyl, and t-butoxycarbonyl(t-BOC). In some embodiments, R¹⁷, R^(17a) and R^(17b) can beindependently H or C₁₋₄ alkyl.

When R¹ is

in some embodiments, A can be a mono-substituted, a poly-substituted oran unsubstituted aryl ring, for example, a mono-substituted, apoly-substituted or an unsubstituted phenyl. In an embodiment, A can bean unsubstituted phenyl. In another embodiment, A can be amono-substituted phenyl. In some embodiments, A can be amono-substituted, a poly-substituted or an unsubstituted heteroarylring. In an embodiment, A can be an unsubstituted heteroaryl ring. Inanother embodiment, A can be a poly-substituted heteroaryl ring. Inother embodiments, A can be a mono-substituted, a poly-substituted or anunsubstituted heterocyclyl ring. In yet still other embodiments, A canbe a mono-substituted, a poly-substituted or an unsubstituted cycloalkylring. In some embodiments, A can be a mono-substituted, apoly-substituted or an unsubstituted cycloalkenyl ring.

Likewise, when R¹ is

in an embodiment, Z¹ can be O (oxygen). In another embodiment, Z¹ can beO(CH₂)₁₋₆. In still another embodiment, Z¹ can be N═N.

In any of the embodiments described with respect to R¹ having thestructure:

R^(12a), R^(12b), R^(12c) and R^(12d) can be each hydrogen.

Examples of

include, but are not limited to, the following:

In some embodiments, R¹ can have the structure:

wherein R^(13a), R^(13b), R^(13c), R^(13d) and R^(13e) can be eachindependently selected from: hydrogen, halo, nitro, cyano, amono-substituted, a poly-substituted or an unsubstituted variant of thefollowing residues: C₁₋₂₄ alkyl, C₂₋₂₄ alkenyl, C₂₋₂₄ alkynyl,mono-haloalkyl, di-haloalkyl, tri-haloalkyl, mono-haloalkoxy,di-haloalkoxy, tri-haloalkoxy, cycloalkyl, cycloalkenyl, cycloalkynyl,aryl, heteroaryl, heterocyclyl, amino, mono-substituted amine,di-substituted amine, alkoxy, acyl, aminoalkyl, salt of an aminoalkyl,carboxyalkyl, a salt of a carboxyalkyl, alkylamino, a salt of analkylamino, dialkylamino, a salt of a dialkylamino, alkylthio, arylthio,carboxy, alkoxysulfinyl, thiocyano, boronic acidalkyl, boronicesteralkyl, sulfoalkyl, a salt of a sulfoalkyl, alkoxysulfonylalkyl,sulfooxyalkyl, a salt of a sulfooxyalkyl, alkoxysulfonyloxyalkyl,phosphonooxyalkyl, a salt of a phosphonooxyalkyl,(alkylphosphooxy)alkyl, phosphorylalkyl, a salt of a phosphorylalkyl,(alkylphosphoryl)alkyl, pyridinylalkyl, a salt of a pyridinylalkyl, asalt of a heteroarylalkyl guanidino, a salt of a guanidino, andguanidinoalkyl.

In some embodiments, R^(13a), R^(13b), R^(13c), R^(13d), and R^(13e) canbe each independently selected from: hydrogen, halo, nitro, cyano, amono-substituted, a poly-substituted or an unsubstituted variant of thefollowing residues: C₁₋₂₄ alkyl, cycloalkyl, cycloalkenyl, aryl,heteroaryl, heterocyclyl, mono-haloalkyl, di-haloalkyl, tri-haloalkyl,mono-haloalkoxy, di-haloalkoxy, tri-haloalkoxy, amino, mono-substitutedamine, di-substituted amine, alkoxy, carboxy and hydroxy.

In some embodiments, when R¹ has the structure:

the phenyl ring of R¹ can be an unsubstituted phenyl ring, anortho-substituted phenyl ring, a meta-substituted phenyl ring or apara-substituted phenyl ring. In some embodiments, at least one ofR^(13a), R^(13b), R^(13c), R^(13d), and R^(13e) is not hydrogen. Inother embodiments, at least two of R^(13a), R^(13b), R^(13c), R^(13d),and R^(13e) are not hydrogen. In still other embodiments, at least threeof R^(13a), R^(13b), R^(13c), R^(13d), and R^(13e) are not hydrogen. Inyet sill other embodiments, at least four of R^(13a), R^(13b), R^(13c),R^(13d), and R^(13e) are not hydrogen. In an embodiment, R^(13c) is nothydrogen. In an embodiment, when R^(13c) is an aryl ring, the aryl ringcan be an optionally substituted phenyl ring. In another embodiment,when R^(13c) is an aryl ring, the aryl ring can be an unsubstitutedphenyl ring. In some embodiments, at least one of R^(13b) or R^(13d) isnot hydrogen. In other embodiments, R^(13c) is not hydrogen and at leastone of R^(13b) or R^(13d) is not hydrogen. Accordingly, the phenyl ringis a para- and meta-substituted phenyl ring. In some embodiments,R^(13c) is not hydrogen and at least one of R^(13a) or R^(13e) is nothydrogen. In an embodiment, the phenyl ring is a para- andortho-substituted phenyl ring.

A non-limiting list of examples of R¹ when R¹ has the structure:

include the following:

In some embodiments, R¹ can have the structure:

wherein: R^(14a), R^(14b) and R^(14c) can be each independently selectedfrom: hydrogen, halo, nitro, cyano, a mono-substituted, apoly-substituted or an unsubstituted variant of the following residues:C₁₋₂₄ alkyl, C₂₋₂₄ alkenyl, C₂₋₂₄ alkynyl, mono-haloalkyl, di-haloalkyl,tri-haloalkyl, mono-haloalkoxy, di-haloalkoxy, tri-haloalkoxy, amino,mono-substituted amine, di-substituted amine, alkoxy, acyl, aminoalkyl,salt of an aminoalkyl, carboxyalkyl, salt of carboxyalkyl,alkylaminoalkyl, salt of an alkylaminoalkyl, dialkylaminoalkyl, salt ofa dialkylaminoalkyl, alkylthioalkyl, arylthioalkyl, carboxy,alkylsulfonylalkyl, alkylsulfinylalkyl, alkoxysulfinylalkyl,thiocyanoalkyl, boronic acidalkyl, boronic esteralkyl, guanidinoalkyl,salt of a guanidinoalkyl, sulfoalkyl, salt of a sulfoalkyl,alkoxysulfonylalkyl, sulfooxyalkyl, salt of a sulfooxyalkyl,alkoxysulfonyloxyalkyl, phosphonooxyalkyl, salt of a phosphonooxyalkyl,(alkylphosphooxy)alkyl, phosphorylalkyl, salt of a phosphorylalkyl,(alkylphosphoryl)alkyl, pyridinylalkyl, salt of a pyridinylalkyl, saltof a heteroarylalkyl; and F can be selected from: a mono-substituted, apoly-substituted or an unsubstituted variant of the following residues:heterocyclyl, aryl, heteroaryl, cycloalkyl and cycloalkenyl.

In some embodiments, F can be a mono-substituted, a poly-substituted oran unsubstituted aryl ring such as a mono-substituted, apoly-substituted or an unsubstituted phenyl ring. In an embodiment, Fcan be a mono-substituted phenyl. In an other embodiment, F can be anunsubstituted phenyl. In other embodiments, F can be a mono-substituted,a poly-substituted or an unsubstituted heteroaryl ring. In still otherembodiments, F can be a mono-substituted, a poly-substituted or anunsubstituted heterocyclyl ring. In yet still other embodiments, F canbe a mono-substituted, a poly-substituted or an unsubstituted cycloalkylring. In some embodiments, F can be a mono-substituted, apoly-substituted or an unsubstituted cycloalkenyl ring. In someembodiment, including those of this paragraph, R^(14a), R^(14b) andR^(14c) can be each hydrogen.

One example of

In some embodiments, R¹ can have the structure:

wherein: R^(15a), R^(15b) and R^(15c) can be each independently selectedfrom: hydrogen, halo, nitro, cyano, a mono-substituted, apoly-substituted or an unsubstituted variant of the following residues:C₁₋₂₄ alkyl, C₂₋₂₄ alkenyl, C₂₋₂₄ alkynyl, mono-haloalkyl, di-haloalkyl,tri-haloalkyl, mono-haloalkoxy, di-haloalkoxy, tri-haloalkoxy, amino,mono-substituted amine, di-substituted amine, alkoxy, acyl, aminoalkyl,salt of an aminoalkyl, salt of an aminoalkyl, carboxyalkyl, a salt of acarboxyalkyl, alkylamino, a salt of an alkylamino, dialkylamino, a saltof a dialkylamino, alkylthio, arylthio, carboxy, alkoxysulfinyl,thiocyano, boronic acidalkyl, boronic esteralkyl, sulfoalkyl, a salt ofa sulfoalkyl, alkoxysulfonylalkyl, sulfooxyalkyl, a salt of asulfooxyalkyl, alkoxysulfonyloxyalkyl, phosphonooxyalkyl, a salt of aphosphonooxyalkyl, (alkylphosphooxy)alkyl, phosphorylalkyl, a salt of aphosphorylalkyl, (alkylphosphoryl)alkyl, pyridinylalkyl, a salt of apyridinylalkyl, a salt of a heteroarylalkyl guanidino, a salt of aguanidino, and guanidinoalkyl; and G can be selected from: amono-substituted, a poly-substituted or an unsubstituted variant of thefollowing residues: heterocyclyl, aryl, heteroaryl, cycloalkyl andcycloalkenyl.

In some embodiments, G can be a mono-substituted, a poly-substituted oran unsubstituted heterocyclyl ring. In other embodiments, G can be amono-substituted, a poly-substituted or an unsubstituted heteroarylring. In still other embodiments, G can be a mono-substituted, apoly-substituted or an unsubstituted aryl ring (for example, a phenylring). In an embodiment, G can be an unsubstituted phenyl ring. Inanother embodiment, G can be a mono-substituted phenyl ring. In yetstill other embodiments, G can be a mono-substituted, a poly-substitutedor an unsubstituted cycloalkyl ring. In some embodiments, G can be amono-substituted, a poly-substituted or an unsubstituted cycloalkenylring. In any embodiment, when R¹ is

R^(15a), R^(15b) and R^(15c) can be each hydrogen or a C₁₋₂₄ alkyl.

An example of

In some embodiments, R¹ can have the structure:

wherein: R^(16a), R^(16b), R^(16c) and R^(16d) can be each independentlyselected from: hydrogen, halo, nitro, cyano, a mono-substituted, apoly-substituted or an unsubstituted variant of the following residues:C₁₋₂₄ alkyl, C₂₋₂₄ alkenyl, C₂₋₂₄ alkynyl, mono-haloalkyl, di-haloalkyl,tri-haloalkyl, mono-haloalkoxy, di-haloalkoxy, tri-haloalkoxy, amino,mono-substituted amine, di-substituted amine, alkoxy, acyl, aminoalkyl,salt of an aminoalkyl, carboxyalkyl, a salt of a carboxyalkyl,alkylamino, a salt of an alkylamino, dialkylamino, a salt of adialkylamino, alkylthio, arylthio, carboxy, alkoxysulfinyl, thiocyano,boronic acidalkyl, boronic esteralkyl, sulfoalkyl, a salt of asulfoalkyl, alkoxysulfonylalkyl, sulfooxyalkyl, a salt of asulfooxyalkyl, alkoxysulfonyloxyalkyl, phosphonooxyalkyl, a salt of aphosphonooxyalkyl, (alkylphosphooxy)alkyl, phosphorylalkyl, a salt of aphosphorylalkyl, (alkylphosphoryl)alkyl, pyridinylalkyl, a salt of apyridinylalkyl, a salt of a heteroarylalkyl guanidino, a salt of aguanidino, guanidinoalkyl and —S(═O)₂O⁻; A can be selected from: amono-substituted, a poly-substituted or an unsubstituted variant of thefollowing residues: heterocyclyl, aryl, heteroaryl, cycloalkyl andcycloalkenyl; and Z¹ can be selected from: O, S, N═N, O(CH₂)₁₋₆,S(O)₂N(R¹⁷), S(O)₂N(R¹⁷)(CH₂)₁₋₆, C(═O)N(R¹⁷), N(R¹⁷)C(═O),N(R¹⁷)C(═O)(CH₂)₁₋₆, N(R¹⁷)C(═O)O(CH₂)₁₋₆, S(O)₂, C(═O), (CH₂)₁₋₆C(═O),O(CH₂)₁₋₆C(═O), (CH₂)₁₋₆ N(R¹⁷)C(═O), CH═CH—C(═O)N(R¹⁷), CH═CH—C(═O),O(CH₂)₁₋₆O, O(CH₂)₁₋₆ and N(R^(17a))C(═O)N(R^(17b)), wherein R¹⁷,R^(17a) and R^(17b) are independently selected from: H, C₁₋₄ alkyl, asubstituted or unsubstituted benzyl, an allyl, and t-butoxycarbonyl(t-BOC). In an embodiment, R¹⁷, R^(17a) and R^(17b) can be independentlyH or C₁₋₄ alkyl.

In some embodiments, when R¹ is

A can be a mono-substituted, a poly-substituted or an unsubstituted arylring, for example, a mono-substituted, a poly-substituted or anunsubstituted phenyl. In an embodiment, A can be an unsubstitutedphenyl. In another embodiment, A can be a mono-substituted phenyl. Inother embodiments, A can be a mono-substituted, a poly-substituted or anunsubstituted heteroaryl ring. In an embodiment, A can be anunsubstituted heteroaryl ring. In another embodiment, A can be apoly-substituted heteroaryl ring. In still other embodiments, A can be amono-substituted, a poly-substituted or an unsubstituted heterocyclylring. In yet still other embodiments, A can be a mono-substituted, apoly-substituted or an unsubstituted cycloalkyl ring. In someembodiments, A can be a mono-substituted, a poly-substituted or anunsubstituted cycloalkenyl ring.

When R¹ is

in some embodiments, Z¹ can be O. In other embodiments, Z¹ can be N═N.In any of the embodiments described with respect to R¹ having thestructure:

R^(16a), R^(16b), R^(16c) and R^(16d) can be each hydrogen.

In any embodiments described herein, E¹ and E³ can be a substituted orunsubstituted heteroatom selected from O (oxygen) and S (sulfur); E² canbe a substituted or unsubstituted N (nitrogen) or —CH₂—; E⁴ can be asubstituted or unsubstituted heteroatom selected from O, S, and N; andE⁵ can be NH₂, SH or OH. In an embodiment, E⁵ can be OH In someembodiments, including those described in the preceding paragraphs, R³can be selected from a mono-substituted, a poly-substituted or anunsubstituted variant of the following residues: C₁₋₆ alkyl, C₃₋₆cycloalkyl, C₂₋₆ alkenyl, C₃₋₆ cycloalkenyl, aryl, and arylalkyl. In anyof the embodiments described in this and any preceding paragraph, R² canbe selected from a mono-substituted, a poly-substituted or anunsubstituted C₁-C₁₂ alkyl, a mono-substituted, a poly-substituted or anunsubstituted C₃-C₁₂ cycloalkyl, a mono-substituted, a poly-substitutedor an unsubstituted C₃-C₁₂ cycloalkenyl and a mono-substituted, apoly-substituted or an unsubstituted aryl; and R³ can be amono-substituted, a poly-substituted or an unsubstituted C₁₋₆ alkyl. Inan embodiment, R² can be an unsubstituted isopropyl or a cycloalkenyl;and R³ can be methyl. In any of the embodiments described in this andany preceding paragraph, n can be 2.

Examples of

include, but are not limited to, the following:

A non-limiting list of examples of compounds of Formula (I) are shown inthe Table 1.

TABLE 1

E¹/E²/E³/E⁴/E⁵ n R¹ R² R³ O/NH/O/O/OH 2

CH₃ O/NH/O/O/OH 2

CH₃ O/NH/O/O/OH 2

CH₃ O/NH/O/O/OH 2

CH₃ O/NH/O/O/OH 2

CH₃ O/NH/O/O/OH 2

CH₃ O/NH/O/O/OH 2

CH₃ O/NH/O/O/OH 2

CH₃ O/NH/O/O/OH 2

CH₃ O/NH/O/O/OH 2

CH₃ O/NH/O/O/OH 2

CH₃ O/NH/O/O/OH 2

CH₃ O/NH/O/O/OH 2

CH₃ O/NH/O/O/OH 2

CH₃ O/NH/O/O/OH 2

CH₃ O/NH/O/O/OH 2

CH₃ O/NH/O/O/OH 2

CH₃ O/NH/O/O/OH 2

CH₃ O/NH/O/O/OH 2

CH₃ O/NH/O/O/OH 2

CH₃ O/NH/O/O/OH 2

CH₃ O/NH/O/O/OH 2

CH₃ O/NH/O/O/OH 2

CH₃ O/NH/O/O/OH 2

CH₃ O/NH/O/O/OH 2

CH₃ O/NH/O/O/OH 2

CH₃ O/NH/O/O/OH 2

CH₃ O/NH/O/O/OH 2

CH₃ O/NH/O/O/OH 2

CH₃ O/NH/O/O/OH 2

CH₃ O/NH/O/O/OH 2

CH₃ O/NH/O/O/OH 2

CH₃ O/NH/O/O/OH 2

CH₃ O/NH/O/O/OH 2

CH₃ O/NH/O/O/OH 2

CH₃ O/NH/O/O/OH 2

CH₃ O/NH/O/O/OH 2

CH₃ O/NH/O/O/OH 2

CH₃ O/NH/O/O/OH 2

CH₃ O/NH/O/O/OH 2

CH₃ O/NH/O/O/OH 2

CH₃ O/NH/O/O/OH 2

CH₃ O/NH/O/O/OH 2

CH₃ O/NH/O/O/OH 2

CH₃ O/NH/O/O/OH 2

CH₃ O/NH/O/O/OH 2

CH₃ O/NH/O/O/OH 2

CH₃ O/NH/O/O/OH 2

CH₃ O/NH/O/O/OH 2

CH₃ O/NH/O/O/OH 2

CH₃ O/NH/O/O/OH 2

CH₃ O/NH/O/O/OH 2

CH₃ O/NH/O/O/OH 2

CH₃ O/NH/O/O/OH 2

CH₃ O/NH/O/O/OH 2

CH₃ O/NH/O/O/OH 2

CH₃ O/NH/O/O/OH 2

CH₃ O/NH/O/O/OH 2

CH₃ O/NH/O/O/OH 2

CH₃ O/NH/O/O/OH 2

CH₃ O/NH/O/O/OH 2

CH₃ O/NH/O/O/OH 2

CH₃ O/NH/O/O/OH 2

CH₃ O/NH/O/O/OH 2

CH₃ O/NH/O/O/OH 2

CH₃ O/NH/O/O/OH 2

CH₃ O/NH/O/O/OH 2

CH₃ O/NH/O/O/OH 2

CH₃ O/NH/O/O/OH 2

CH₃ O/NH/O/O/OH 2

CH₃ O/NH/O/O/OH 2

CH₃ O/NH/O/O/OH 2

CH₃ O/NH/O/O/OH 2

CH₃ O/NH/O/O/OH 2

CH₃ O/NH/O/O/OH 2

CH₃ O/NH/O/O/OH 2

CH₃ O/NH/O/O/OH 2

CH₃ O/NH/O/O/OH 2

CH₃ O/NH/O/O/OH 2

CH₃ O/NH/O/O/OH 2

CH₃ O/NH/O/O/OH 2

CH₃ O/NH/O/O/OH 2

CH₃ O/NH/O/O/OH 2

CH₃ O/NH/O/O/OH 2

CH₃ O/NH/O/O/OH 2

CH₃ O/NH/O/O/OH 2

CH₃ O/NH/O/O/OH 2

CH₃ O/NH/O/O/OH 2

CH₃ O/NH/O/O/OH 2

CH₃ O/NH/O/O/OH 2

CH₃ O/NH/O/O/OH 2

CH₃ O/NH/O/O/OH 2

CH₃ O/NH/O/O/OH 2

CH₃ O/NH/O/O/OH 2

CH₃ O/NH/O/O/OH 2

CH₃ O/NH/O/O/OH 2

CH₃ O/NH/O/O/OH 2

CH₃ O/NH/O/O/OH 2

CH₃ O/NH/O/O/OH 2

CH₃ O/NH/O/O/OH 2

CH₃ O/NH/O/O/OH 2

CH₃ O/NH/O/O/OH 2

CH₃ O/NH/O/O/OH 2

CH₃ O/NH/O/O/OH 2

CH₃ O/NH/O/O/OH 2

CH₃ O/NH/O/O/OH 2

CH₃ O/NH/O/O/OH 2

CH₃ O/NH/O/O/OH 2

CH₃ O/NH/O/O/OH 2

CH₃ O/NH/O/O/OH 2

CH₃ O/NH/O/O/OH 2

CH₃ O/NH/O/O/OH 2

CH₃ O/NH/O/O/OH 2

CH₃ O/NH/O/O/OH 2

CH₃ O/NH/O/O/OH 2

CH₃ O/NH/O/O/OH 2

CH₃ O/NH/O/O/OH 2

CH₃ O/NH/O/O/OH 2

CH₃ O/NH/O/O/OH 2

CH₃ O/NH/O/O/OH 2

CH₃ O/NH/O/O/OH 2

CH₃ O/NH/O/O/OH 2

CH₃ O/NH/O/O/OH 2

CH₃ O/NH/O/O/OH 2

CH₃ O/NH/O/O/OH 2

CH₃ O/NH/O/O/OH 2

CH₃ O/NH/O/O/OH 2

CH₃ O/NH/O/O/OH 2

CH₃ O/NH/O/O/OH 2

CH₃ O/NH/O/O/OH 2

CH₃ O/NH/O/O/OH 2

CH₃ O/NH/O/O/OH 2

CH₃ O/NH/O/O/OH 2

CH₃ O/NH/O/O/OH 2

CH₃ O/NH/O/O/OH 2

CH₃ O/NH/O/O/OH 2

CH₃ O/NH/O/O/OH 2

CH₃ O/NH/O/O/OH 2

CH₃ O/NH/O/O/OH 2

CH₃ O/NH/O/O/OH 2

CH₃ O/NH/O/O/OH 2

CH₃ O/NH/O/O/OH 2

CH₃ O/NH/O/O/OH 2

CH₃ O/NH/O/O/OH 2

CH₃ O/NH/O/O/OH 2

CH₃ O/NH/O/O/OH 2

CH₃ O/NH/O/O/OH 2

CH₃ O/NH/O/O/OH 2

CH₃ O/NH/O/O/OH 2

CH₃ O/NH/O/O/OH 2

CH₃ O/NH/O/O/OH 2

CH₃ O/NH/O/O/OH 2

CH₃ O/NH/O/O/OH 2

CH₃ O/NH/O/O/OH 2

CH₃ O/NH/O/O/OH 2

CH₃ O/NH/O/O/OH 2

CH₃ O/NH/O/O/OH 2

CH₃ O/NH/O/O/OH 2

CH₃ O/NH/O/O/OH 2

CH₃ O/NH/O/O/OH 2

CH₃ O/NH/O/O/OH 2

CH₃ O/NH/O/O/OH 2

CH₃ O/NH/O/O/OH 2

CH₃ O/NH/O/O/OH 2

CH₃ O/NH/O/O/OH 2

CH₃ O/NH/O/O/OH 2

CH₃ O/NH/O/O/OH 2

CH₃ O/NH/O/O/OH 2

CH₃ O/NH/O/O/OH 2

CH₃ O/NH/O/O/OH 2

CH₃ O/NH/O/O/OH 2

CH₃ O/NH/O/O/OH 2

CH₃ O/NH/O/O/OH 2

CH₃ O/NH/O/O/OH 2

CH₃ O/NH/O/O/OH 2

CH₃ O/NH/O/O/OH 2

CH₃ O/NH/O/O/OH 2

CH₃ O/NH/O/O/OH 2

CH₃ O/NH/O/O/OH 2

CH₃ O/NH/O/O/OH 2

CH₃ O/NH/O/O/OH 2

CH₃ O/NH/O/O/OH 2

CH₃ O/NH/O/O/OH 2

CH₃ O/NH/O/O/OH 2

CH₃ O/NH/O/O/OH 2

CH₃ O/NH/O/O/OH 2

CH₃ O/NH/O/O/OH 2

CH₃ O/NH/O/O/OH 2

CH₃ O/NH/O/O/OH 2

CH₃ O/NH/O/O/OH 2

CH₃ O/NH/O/O/OH 2

CH₃ O/NH/O/O/OH 2

CH₃ O/NH/O/O/OH 2

CH₃ O/NH/O/O/OH 2

CH₃ O/NH/O/O/OH 2

CH₃ O/NH/O/O/OH 2

CH₃ O/NH/O/O/OH 2

CH₃ O/NH/O/O/OH 2

CH₃ O/NH/O/O/OH 2

CH₃ O/NH/O/O/OH 2

CH₃ O/NH/O/O/OH 2

CH₃ O/NH/O/O/OH 2

CH₃ O/NH/O/O/OH 2

CH₃ O/NH/O/O/OH 2

CH₃ O/NH/O/O/OH 2

CH₃ O/NH/O/O/OH 2

CH₃ O/NH/O/O/OH 2

CH₃ O/NH/O/O/OH 2

CH₃ O/NH/O/O/OH 2

CH₃ O/NH/O/O/OH 2

CH₃ O/NH/O/O/OH 2

CH₃ O/NH/O/O/OH 2

CH₃ O/NH/O/O/OH 2

CH₃ O/NH/O/O/OH 2

CH₃ O/NH/O/O/OH 2

CH₃ O/NH/O/O/OH 2

CH₃ O/NH/O/O/OH 2

CH₃ O/NH/O/O/OH 2

CH₃ O/NH/O/O/OH 2

CH₃ O/NH/O/O/OH 2

CH₃ O/NH/O/O/OH 2

CH₃ O/NH/O/O/OH 2

CH₃ O/NH/O/O/OH 2

CH₃ O/NH/O/O/OH 2

CH₃ O/NH/O/O/OH 2

CH₃ O/NH/O/O/OH 2

CH₃ O/NH/O/O/OH 2

CH₃ O/NH/O/O/OH 2

CH₃ O/NH/O/O/OH 2

CH₃ O/NH/O/O/OH 2

CH₃ O/NH/O/O/OH 2

CH₃ O/NH/O/O/OH 2

CH₃ O/NH/O/O/OH 2

CH₃ O/NH/O/O/OH 2

CH₃ O/NH/O/O/OH 2

CH₃ O/NH/O/O/OH 2

CH₃ O/NH/O/O/OH 2

CH₃ O/NH/O/O/OH 2

CH₃ O/NH/O/O/OH 2

CH₃ O/NH/O/O/OH 2

CH₃ O/NH/O/O/OH 2

CH₃ O/NH/O/O/OH 2

CH₃ O/NH/O/O/OH 2

CH₃ O/NH/O/O/OH 2

CH₃ O/NH/O/O/OH 2

CH₃ O/NH/O/O/OH 2

CH₃ O/NH/O/O/OH 2

CH₃ O/NH/O/O/OH 2

CH₃ O/NH/O/O/OH 2

CH₃ O/NH/O/O/OH 2

CH₃ O/NH/O/O/OH 2

CH₃ O/NH/O/O/OH 2

CH₃ O/NH/O/O/OH 2

CH₃ O/NH/O/O/OH 2

CH₃ O/NH/O/O/OH 2

CH₃ O/NH/O/O/OH 2

CH₃ O/NH/O/O/OH 2

CH₃ O/NH/O/O/OH 2

CH₃ O/NH/O/O/OH 2

CH₃ O/NH/O/O/OH 2

CH₃ O/NH/O/O/OH 2

CH₃ O/NH/O/O/OH 2

CH₃ O/NH/O/O/OH 2

CH₃ O/NH/O/O/OH 2

CH₃Synthesis

Compounds of Formula (I), and those described herein may be prepared invarious ways. General synthetic routes to the compounds of Formula (I),and examples of starting materials that can be used to synthesize thecompounds of Formula (I) are shown in Schemes 2, 3 and 4. The routesshown are illustrative only and are not intended, nor are they to beconstrued, to limit the scope of the claims in any manner whatsoever.Those skilled in the art will be able to recognize modifications of thedisclosed synthesis and to devise alternate routes based on thedisclosures herein; all such modifications and alternate routes arewithin the scope of the claims.

The halogen of a compound of Formula (A), denoted by X^(A), can bereplaced with a hydroxy group to form a compound of Formula (B) usingone or more synthetic routes, such as the routes disclosed in U.S. Pat.No. 7,276,430; U.S. Publication Nos. 2005-0049294, 2007-0249693,2005-0228186 and 2006-0287520; and PCT Publication Nos. WO 2006/060809,WO 2007/117591 and WO 2005/099687. A compound of Formula (A) can beobtained made using methods described in U.S. Pat. No. 7,276,430; U.S.Publication Nos. 2005-0049294, 2007-0249693, 2005-0228186 and2006-0287520; and PCT Publication Nos. WO 2006/060809, WO 2007/117591and WO 2005/099687. Alternatively, a compound of Formula (B) can besynthesized by treating a compound of Formula (A) with a silver reagentto form a compound of Formula (B). In an embodiment, X^(A) can be iodo.Suitable silver reagents that can be used include, but are not limitedto, silver fluoride (Ag—F) and AgF—CaF₂. Treatment of a compound ofFormula (A) with a silver reagent provides a method for obtaining acompound of Formula (B) with good yields.

In some embodiments, for compounds of Formulae (A) and (B), R^(A) can beselected from: a hydrogen, a halogen, cyano, a mono-substituted, apoly-substituted or an unsubstituted variant of the following residues:C₁-C₁₂ alkyl, C₂-C₁₂ alkenyl, C₂-C₁₂ alkynyl, C₃-C₁₂ cycloalkyl, C₃-C₁₂cycloalkenyl, C₃-C₁₂ cycloalkynyl, C₃-C₁₂ heterocyclyl, aryl,heteroaryl, arylalkyl, heteroarylalkyl, (cycloalkyl)alkyl,(heterocyclyl)alkyl, acyl, acylalkyl, alkyloxycarbonyloxy, carbonylacyl,aminocarbonyl, azido, azidoalkyl, mono-haloalkyl, di-haloakyl,tri-haloalkyl, aminoalkyl, salt of an aminoalkyl, carboxyalkyl, a saltof a carboxyalkyl, alkylamino, a salt of an alkylamino, dialkylamino, asalt of a dialkylamino, alkylthio, arylthio, carboxy, alkoxysulfinyl,thiocyano, boronic acidalkyl, boronic esteralkyl, sulfoalkyl, a salt ofa sulfoalkyl, alkoxysulfonylalkyl, sulfooxyalkyl, a salt of asulfooxyalkyl, alkoxysulfonyloxyalkyl, phosphonooxyalkyl, a salt of aphosphonooxyalkyl, (alkylphosphooxy)alkyl, phosphorylalkyl, a salt of aphosphorylalkyl, (alkylphosphoryl)alkyl, pyridinylalkyl, a salt of apyridinylalkyl, a salt of a heteroarylalkyl guanidino, a salt of aguanidino, and guanidinoalkyl; R^(B) can be selected from hydrogen,halogen, a mono-substituted, a poly-substituted or an unsubstitutedvariant of the following residues: C₁₋₆ alkyl, C₃₋₆ cycloalkyl, C₂₋₆alkenyl, C₃₋₆ cycloalkenyl, aryl, and arylalkyl; m can be 1, 2 or 3;E^(A), E^(C), E^(D) and E^(E) can be each independently a substituted orunsubstituted heteroatom; E^(B) can be a substituted or unsubstitutedheteroatom (such as NH) or —CH₂— group; and X^(A) can be halogen. Insome embodiments, E^(E) can be NH₂, OH or SH. In an embodiment, E^(E)can be OH.

A compound of Formula (B) can then be reacted with a compound thatcontains a sulfonyl moiety, for example,

to form a compound of Formula (I), wherein R¹ is

Similarly, a compound of Formula (B) can be reacted with a compound thatcontains a carboxylic acid or acid chloride moiety, such as

to form a compound of Formula (I), wherein R¹ is

For compounds having the structure:

R^(C) can be selected from a mono-substituted, a poly-substituted or anunsubstituted variant of the following residues: aryl, aryl(C₁₋₆ alkyl),heteroaryl, heteroaryl(C₁₋₆ alkyl), heterocyclyl, and heterocyclyl(C₁₋₆alkyl), wherein R^(C) can be optionally substituted with can beoptionally substituted with

wherein A can be selected from a mono-substituted, a poly-substituted oran unsubstituted variant of the following residues: heterocyclyl, aryland heteroaryl; and Z¹ can be selected from O (oxygen), S (sulfur), N═N,O(CH₂)₁₋₆, S(O)₂N(R¹⁷), S(O)₂N(R¹⁷)(CH₂)₁₋₆, C(═O)N(R¹⁷), N(R¹⁷)C(═O),N(R¹⁷)C(═O)(CH₂)₁₋₆, N(R¹⁷)C(═O)O(CH₂)₁₋₆, S(O)₂, C(═O), (CH₂)₁₋₆C(═O),O(CH₂)₁₋₆C(═O), (CH₂)₁₋₆ N(R¹⁷)C(═O), CH═CH—C(═O)N(R¹⁷), CH═CH—C(═O),O(CH₂)₁₋₆O, O(CH₂)₁₋₆ and N(R^(17a))C(═O)N(R^(17b)), wherein R¹⁷,R^(17a) and R^(17b) can be independently selected from: H, C₁₋₄ alkyl, asubstituted or unsubstituted benzyl, an allyl, and t-butoxycarbonyl(t-BOC); and X^(B) can be a leaving group or hydroxy. In an embodiment,X^(B) can be a halogen. In some embodiments, a base can be used tofacilitate the reaction. Suitable bases are known to those skilled inthe art, and include, but are not limited to, amine-based bases, such asdiethylamide and pyridine, or pyridine based bases, such as4-(dimethylamino)pyridine (DMAP). In some embodiments, a dehydratingagent such as N,N′-dicyclohexylcarbodiimide (DCC) or1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (EDC) can be used alongwith one or more of the aforementioned bases to facilitate the formationof the carboxylic esters from carboxylic acids.

A compound of Formula (I) with R¹ having the structure

can be obtained starting with a compound of Formula (C) that has aleaving group, such as a sulfonate ester or halogen, at the equivalentposition of R¹ for a compound of Formula (I). As shown in Scheme 4, acompound of Formula (C) can be reacted with a base and a compound havingthe structure X^(B)—R^(C), wherein R^(C) can be selected from amono-substituted, a poly-substituted or an unsubstituted variant of thefollowing residues: aryl, aryl(C₁₋₆ alkyl), heteroaryl, heteroaryl(C₁₋₆alkyl), heterocyclyl, and heterocyclyl(C₁₋₆ alkyl), wherein R^(C) can beoptionally substituted with

wherein A can be selected from a mono-substituted, a poly-substituted oran unsubstituted variant of the following residues: heterocyclyl, aryland heteroaryl; and Z¹ can be selected from O (oxygen), S (sulfur), N═N,O(CH₂)₁₋₆, S(O)₂N(R¹⁷), S(O)₂N(R¹⁷)(CH₂)₁₋₆, C(═O)N(R¹⁷), N(R¹⁷)C(═O),N(R¹⁷)C(═O)(CH₂)₁₋₆, N(R¹⁷)C(═O)O(CH₂)₁₋₆, S(O)₂, C(═O), (CH₂)₁₋₆C(═O),O(CH₂)₁₋₆C(═O), (CH₂)₁₋₆ N(R¹⁷)C(═O), CH═CH—C(═O)N(R¹⁷), CH═CH—C(═O),O(CH₂)₁₋₆O, O(CH₂)₁₋₆ and N(R^(17a))C(═O)N(R^(17b)), wherein R¹⁷,R^(17a) and R^(17b) can be independently selected from: H, C₁₋₄ alkyl, asubstituted or unsubstituted benzyl, an allyl, and t-butoxycarbonyl(t-BOC); and X^(B) can be a leaving group or hydroxy, to form a compoundof Formula (I) that has a

moiety at R¹. Examples of suitable bases include, but are not limitedto, sodium hydride, potassium hydride, lithium hydride, potassiumtert-butoxide lithium diisopropylamide (LDA), butyl lithium and calciumhydride. In some embodiments, a compound of Formula (I) where R¹ is

can be obtained starting with a compound of Formula (A), synthesizing acompound of Formula (B) as described herein, obtaining a compound ofFormula (I) where R¹ is

using one of the procedures described herein, and then reacting thecompound of Formula (I) where R¹ is

with a compound having the structure X^(B)—R^(C) wherein R^(C) can beselected from a mono-substituted, a poly-substituted or an unsubstitutedvariant of the following residues: aryl, aryl(C₁₋₆ alkyl), heteroaryl,heteroaryl(C₁₋₆ alkyl), heterocyclyl, and heterocyclyl(C₁₋₆ alkyl),wherein R^(C) can be optionally substituted with

wherein A can be selected from a mono-substituted, a poly-substituted oran unsubstituted variant of the following residues: heterocyclyl, aryland heteroaryl; and Z¹ can be selected from O (oxygen), S (sulfur), N═N,O(CH₂)₁₋₆, S(O)₂N(R¹⁷), S(O)₂N(R¹⁷)(CH₂)₁₋₆, C(═O)N(R¹⁷), N(R¹⁷)C(═O),N(R¹⁷)C(═O)(CH₂)₁₋₆, N(R¹⁷)C(═O)O(CH₂)₁₋₆, S(O)₂, C(═O), (CH₂)₁₋₆C(═O),O(CH₂)₁₋₆C(═O), (CH₂)₁₋₆ N(R¹⁷)C(═O), CH═CH—C(═O)N(R¹⁷), CH═CH—C(═O),O(CH₂)₁₋₆O, O(CH₂)₁₋₆ and N(R^(17a))C(═O)N(R^(17b)), wherein R¹⁷,R^(17a) and R^(17b) can be independently selected from: H, C₁₋₄ alkyl, asubstituted or unsubstituted benzyl, an allyl, and t-butoxycarbonyl(t-BOC); and X^(B) can be a leaving group or hydroxy. A compound ofFormula (I), where R¹ is

can also be obtained by reacting a compound of Formula (A) withX^(B)—R^(C).Pharmaceutical Compositions

An embodiment described herein relates to a pharmaceutical composition,that can include a therapeutically effective amount of one or morecompounds described herein (e.g., a compound of Formula (I)), and apharmaceutically acceptable carrier, diluent, excipient or combinationthereof.

The term “pharmaceutical composition” refers to a mixture of a compounddisclosed herein with other chemical components, such as diluents orcarriers. The pharmaceutical composition facilitates administration ofthe compound to an organism. Multiple techniques of administering acompound exist in the art including, but not limited to, oral,intramuscular, intraocular, intranasal, intravenous, injection, aerosol,parenteral, and topical administration. Pharmaceutical compositions canalso be obtained by reacting compounds with inorganic or organic acidssuch as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid,phosphoric acid, methanesulfonic acid, ethanesulfonic acid,p-toluenesulfonic acid, salicylic acid and the like. Pharmaceuticalcompositions will generally be tailored to the specific intended routeof administration.

The term “physiologically acceptable” defines a carrier, diluent orexcipient that does not abrogate the biological activity and propertiesof the compound.

As used herein, a “carrier” refers to a compound that facilitates theincorporation of a compound into cells or tissues. For example, withoutlimitation, dimethyl sulfoxide (DMSO) is a commonly utilized carrierthat facilitates the uptake of many organic compounds into cells ortissues of a subject.

As used herein, a “diluent” refers to an ingredient in a pharmaceuticalcomposition that lacks pharmacological activity but may bepharmaceutically necessary or desirable. For example, a diluent may beused to increase the bulk of a potent drug whose mass is too small formanufacture or administration. It may also be a liquid for thedissolution of a drug to be administered by injection, ingestion orinhalation. A common form of diluent in the art is a buffered aqueoussolution such as, without limitation, phosphate buffered saline thatmimics the composition of human blood.

As used herein, an “excipient” refers to an inert substance that isadded to a pharmaceutical composition to provide, without limitation,bulk, consistency, stability, binding ability, lubrication,disintegrating ability etc., to the composition. A “diluent” is a typeof excipient.

The pharmaceutical compositions described herein can be administered toa human patient per se, or in pharmaceutical compositions where they aremixed with other active ingredients, as in combination therapy, orcarriers, diluents, excipients or combinations thereof. Properformulation is dependent upon the route of administration chosen.Techniques for formulation and administration of the compounds describedherein are known to those skilled in the art.

The pharmaceutical compositions disclosed herein may be manufactured ina manner that is itself known, e.g., by means of conventional mixing,dissolving, granulating, dragee-making, levigating, emulsifying,encapsulating, entrapping or tableting processes. Additionally, theactive ingredients are contained in an amount effective to achieve itsintended purpose. Many of the compounds used in the pharmaceuticalcombinations disclosed herein may be provided as salts withpharmaceutically compatible counterions.

Suitable routes of administration may, for example, include oral,rectal, topical transmucosal, or intestinal administration; parenteraldelivery, including intramuscular, subcutaneous, intravenous,intramedullary injections, as well as intrathecal, directintraventricular, intraperitoneal, intranasal, intraocular injections oras an aerosol inhalant.

One may also administer the compound in a local rather than systemicmanner, for example, via injection of the compound directly into theinfected area, often in a depot or sustained release formulation.Furthermore, one may administer the compound in a targeted drug deliverysystem, for example, in a liposome coated with a tissue-specificantibody. The liposomes will be targeted to and taken up selectively bythe organ.

The compositions may, if desired, be presented in a pack or dispenserdevice which may contain one or more unit dosage forms containing theactive ingredient. The pack may for example comprise metal or plasticfoil, such as a blister pack. The pack or dispenser device may beaccompanied by instructions for administration. The pack or dispensermay also be accompanied with a notice associated with the container inform prescribed by a governmental agency regulating the manufacture,use, or sale of pharmaceuticals, which notice is reflective of approvalby the agency of the form of the drug for human or veterinaryadministration. Such notice, for example, may be the labeling approvedby the U.S. Food and Drug Administration for prescription drugs, or theapproved product insert. Compositions that include a compound disclosedherein formulated in a compatible pharmaceutical carrier may also beprepared, placed in an appropriate container, and labeled for treatmentof an indicated condition.

Methods of Use

One embodiment disclosed herein relates to a method of treating and/orameliorating a disease or condition that can include administering to asubject a therapeutically effective amount of one or more compoundsdescribed herein, such as a compound of Formula (I), or a pharmaceuticalcomposition that includes a compound described herein (for example, acompound of Formula (I)).

Some embodiments disclosed herein relate to a method of ameliorating ortreating a neoplastic disease that can include administering to asubject suffering from the neoplastic disease a therapeuticallyeffective amount of one or more compounds described herein (e.g., acompound of Formula (I)), a pharmaceutically acceptable salt, prodrugand/or a pro-drug ester thereof, or a pharmaceutical composition thatincludes one or more compounds described herein. In an embodiment, theneoplastic disease can be cancer. Examples of some types of cancer thatcan be treated and/or ameliorated with a therapeutically effectiveamount of one or more compounds described herein, such as a compound ofFormula (I) include, but are not limited to, breast cancer, sarcoma,leukemia, ovarian cancer, bladder cancer, prostate cancer, colon cancer,rectal cancer, stomach cancer, lung cancer, lymphoma (such as Hodgkin'slymphoma, non-Hodgkin's lymphoma), multiple myeloma, pancreatic cancer,kidney cancer, endocrine cancer, melanoma, skin cancer, angiosarcoma,sinus cancer, esophageal cancer, uretal cancer, liver cancer, angioma,central nervous system (CNS) cancer (including brain cancer), Mantlecell lymphoma, low IgM secreting lymphoma, Burkitt's lymphoma, B-NHL andWaldenstrom's Macroglobulinemia. In some embodiments, the cancer can beselected from multiple myeloma, a colorectal carcinoma, a prostatecarcinoma, a breast adenocarcinoma, a non-small cell lung carcinoma, anovarian carcinoma, and a melanoma. In an embodiment, the cancer can bemultiple myeloma.

The cancer also can be a drug-resistant cancer. In some instances, thedrug-resistant cancer may display at least one of the following:elevated levels of the P-glycoprotein efflux pump, increased expressionof the multidrug-resistance associated protein 1 encoded by MRP1,reduced drug uptake, alteration of the drug's target or increasingrepair of drug-induced DNA damage, alteration of the apoptotic pathwayor the activation of cytochrome P450 enzymes. In an embodiment, the drugresistant cancer can be a sarcoma and/or leukemia.

Still further embodiments relate to methods of inhibiting the growth ofa cancer cell. The methods can include, for example, contacting a cancercell with a compound a pharmaceutically acceptable salt, prodrug and/ora pro-drug ester thereof, or a pharmaceutical composition describedherein. A non-limiting list of cancer cells include a breast cancercell, a sarcoma cell, a leukemia cell, an ovarian cancer cell, a bladdercancer cell, a prostate cancer cell, a colon cancer cell, a rectalcancer cell, a stomach cancer cell, a lung cancer cell, a lymphoma cell,a multiple myeloma cell, a pancreatic cancer cell, a kidney cancer cell,an endocrine cancer cell, a melanoma cell, a skin cancer cell, anangiosarcoma cell, a sinus cancer cell, an esophageal cancer cell, anuretal cancer cell, a liver cancer cell, an angioma cell, a centralnervous system (CNS) cancer cell (including a brain cancer cell). In anembodiment, the cancer cell may be, for example, a multiple myelomacell, a colorectal carcinoma cell, a prostate carcinoma cell, a breastadenocarcinoma cell, a non-small cell lung carcinoma cell, an ovariancarcinoma cell, a melanoma cell, and the like.

Other embodiments relate to methods of inhibiting proteasome activitycomprising the step contacting a cell with one or more compoundsdescribed herein (e.g., a compound of Formula (I)), a pharmaceuticallyacceptable salt, prodrug and/or a pro-drug ester thereof, or apharmaceutical composition that includes one or more compounds describedherein.

Further embodiments relate to methods of inhibiting NF-κB activation.The methods can include, for example, the step contacting a cell withone or more compounds described herein (e.g., a compound of Formula(I)), a pharmaceutically acceptable salt, prodrug and/or a pro-drugester thereof, or a pharmaceutical composition that includes one or morecompounds described herein.

Still other embodiments relate to methods for treating an inflammatorycondition. The methods may include, for example, administering aneffective amount of one or more compounds described herein (e.g., acompound of Formula (I)), a pharmaceutically acceptable salt, prodrugand/or a pro-drug ester thereof, or a pharmaceutical composition thatincludes one or more compounds described herein to a subject sufferingfrom an inflammatory condition. An “inflammatory condition” includes,for example, conditions such as ischemia, septic shock, autoimmunediseases, rheumatoid arthritis, inflammatory bowel disease, systemiclupus eythematosus, multiple sclerosis, asthma, osteoarthritis,osteoporosis, fibrotic diseases, dermatosis, including psoriasis, atopicdermatitis and ultraviolet radiation (UV)-induced skin damage, psoriaticarthritis, alkylosing spondylitis, tissue and organ rejection,Alzheimer's disease, stroke, atherosclerosis, restenosis, diabetes,glomerulonephritis, cancer, Hodgkins disease, cachexia, inflammationassociated with infection and certain viral infections, includingacquired immune deficiency syndrome (AIDS), adult respiratory distresssyndrome and Ataxia Telangiestasia. In some embodiments, theinflammatory condition can be selected from rheumatoid arthritis,asthma, multiple sclerosis, psoriasis, stroke, myocardial infarction,and the like.

Some embodiments relate to methods for treating a microbial illnesswhich can include administering an effective amount of one or morecompounds described herein (e.g., a compound of Formula (I)), apharmaceutically acceptable salt, prodrug and/or a pro-drug esterthereof, or a pharmaceutical composition that includes one or morecompounds described herein to a subject suffering from a microbialillness. The microbial illness maybe caused, for example by B.anthracis, Plasmodium, Leishmania, Trypanosoma, Mycobacterium Bovis,Mycobacterium africanum and Mycobacterium microti. Examples of microbialillness include, but are not limited to the following: Bacteremia,Botulism, Brucellosis, Clostridium Difficile, Campylobacter Infection,Cat Scratch Disease, Chancroid, Chlamydia, Cholera, ClostridiumPerfringens, Bacterial Conjunctivitis, Diphtheria, E. Coli Infections,Ehrlichiosis, Epididymitis, Gardnerella, Gas Gangrene, Gonorrhea,Helicobacter Pylori, Haemophilus, Influenzae B, Impetigo, Intertrigo,Leprosy, Listeriosis, Lyme Disease, Methicillin Resistant StaphylococcusAureus, Orchitis, Osteomyelitis, Otitis, Media Pertussis, Plague,Pneumonia, Prostatitis Pyelonephritis, Q Fever, Rocky Mountain SpottedFever, Salmonellosis, Scarlet Fever, Sepsis, Shigellosis, StaphylococcalInfections, Streptococcal Infections, Syphilis, Tetanus, Toxic ShockSyndrome, Trachoma, Traveller's Diarrhea, Tuberculosis, Tularemia,Typhoid Fever, Typhus Fever, Urinary Tract Infections, BacterialVaginosis, Pertussis, Yersiniosis, malaria, African trypanosomiasis,candidiasis, histoplasmosis, blastomycosis, coccidioidomycosis,aspergillisis, and mucormycosis.

As used herein, a “subject” refers to an animal that is the object oftreatment, observation or experiment. “Animal” includes cold- andwarm-blooded vertebrates and invertebrates such as fish, shellfish,reptiles and, in particular, mammals. “Mammal” includes, withoutlimitation, mice, rats, rabbits, guinea pigs, dogs, cats, sheep, goats,cows, horses, primates, such as monkeys, chimpanzees, and apes, and, inparticular, humans.

As used herein, the terms “treating,” “treatment,” “therapeutic,” or“therapy” do not necessarily mean total cure or abolition of the diseaseor condition. Any alleviation of any undesired signs or symptoms of adisease or condition, to any extent can be considered treatment and/ortherapy. Furthermore, treatment may include acts that may worsen thepatient's overall feeling of well-being or appearance.

The term “therapeutically effective amount” is used to indicate anamount of an active compound, or pharmaceutical agent, that elicits thebiological or medicinal response indicated. For example, atherapeutically effective amount of compound can be the amount need toprevent, alleviate or ameliorate symptoms of disease or prolong thesurvival of the subject being treated This response may occur in atissue, system, animal or human and includes alleviation of the symptomsof the disease being treated. Determination of a therapeuticallyeffective amount is well within the capability of those skilled in theart, especially in light of the detailed disclosure provided herein. Thetherapeutically effective amount of the compounds disclosed hereinrequired as a dose will depend on the route of administration, the typeof animal, including human, being treated, and the physicalcharacteristics of the specific animal under consideration. The dose canbe tailored to achieve a desired effect, but will depend on such factorsas weight, diet, concurrent medication and other factors which thoseskilled in the medical arts will recognize.

As will be readily apparent to one skilled in the art, the useful invivo dosage to be administered and the particular mode of administrationwill vary depending upon the age, weight, the severity of theaffliction, and mammalian species treated, the particular compoundsemployed, and the specific use for which these compounds are employed.(See e.g., Fingl et al. 1975, in “The Pharmacological Basis ofTherapeutics”, which is hereby incorporated herein by reference in itsentirety, with particular reference to Ch. 1, p. 1). The determinationof effective dosage levels, that is the dosage levels necessary toachieve the desired result, can be accomplished by one skilled in theart using routine pharmacological methods. Typically, human clinicalapplications of products are commenced at lower dosage levels, withdosage level being increased until the desired effect is achieved.Alternatively, acceptable in vitro studies can be used to establishuseful doses and routes of administration of the compositions identifiedby the present methods using established pharmacological methods.

Although the exact dosage will be determined on a drug-by-drug basis, inmost cases, some generalizations regarding the dosage can be made. Thedaily dosage regimen for an adult human patient may be, for example, anoral dose of between 0.01 mg and 3000 mg of each active ingredient,preferably between 1 mg and 700 mg, e.g. 5 to 200 mg. The dosage may bea single one or a series of two or more given in the course of one ormore days, as is needed by the patient. In some embodiments, thecompounds will be administered for a period of continuous therapy, forexample for a week or more, or for months or years.

In instances where human dosages for compounds have been established forat least some condition, those same dosages, or dosages that are betweenabout 0.1% and 500%, more preferably between about 25% and 250% of theestablished human dosage will be used. Where no human dosage isestablished, as will be the case for newly-discovered pharmaceuticalcompositions, a suitable human dosage can be inferred from ED₅₀ or ID₅₀values, or other appropriate values derived from in vitro or in vivostudies, as qualified by toxicity studies and efficacy studies inanimals.

In cases of administration of a pharmaceutically acceptable salt,dosages may be calculated as the free base. As will be understood bythose of skill in the art, in certain situations it may be necessary toadminister the compounds disclosed herein in amounts that exceed, oreven far exceed, the above-stated, preferred dosage range in order toeffectively and aggressively treat particularly aggressive diseases orinfections.

Dosage amount and interval may be adjusted individually to provideplasma levels of the active moiety which are sufficient to maintain themodulating effects, or minimal effective concentration (MEC). The MECwill vary for each compound but can be estimated from in vitro data.Dosages necessary to achieve the MEC will depend on individualcharacteristics and route of administration. However, HPLC assays orbioassays can be used to determine plasma concentrations.

Dosage intervals can also be determined using MEC value. Compositionsshould be administered using a regimen which maintains plasma levelsabove the MEC for 10-90% of the time, preferably between 30-90% and mostpreferably between 50-90%. In cases of local administration or selectiveuptake, the effective local concentration of the drug may not be relatedto plasma concentration.

It should be noted that the attending physician would know how to andwhen to terminate, interrupt, or adjust administration due to toxicityor organ dysfunctions. Conversely, the attending physician would alsoknow to adjust treatment to higher levels if the clinical response werenot adequate (precluding toxicity). The magnitude of an administrateddose in the management of the disorder of interest will vary with theseverity of the condition to be treated and to the route ofadministration. The severity of the condition may, for example, beevaluated, in part, by standard prognostic evaluation methods. Further,the dose and perhaps dose frequency, will also vary according to theage, body weight, and response of the individual patient. A programcomparable to that discussed above may be used in veterinary medicine.

In non-human animal studies, applications of potential products arecommenced at higher dosage levels, with dosage being decreased until thedesired effect is no longer achieved or adverse side effects disappear.The dosage may range broadly, depending upon the desired effects and thetherapeutic indication. Alternatively dosages may be based andcalculated upon the surface area of the patient, as understood by thoseof skill in the art.

Compounds disclosed herein can be evaluated for efficacy and toxicityusing known methods. For example, the toxicology of a particularcompound, or of a subset of the compounds, sharing certain chemicalmoieties, may be established by determining in vitro toxicity towards acell line, such as a mammalian, and preferably human, cell line. Theresults of such studies are often predictive of toxicity in animals,such as mammals, or more specifically, humans. Alternatively, thetoxicity of particular compounds in an animal model, such as mice, rats,rabbits, or monkeys, may be determined using known methods. The efficacyof a particular compound may be established using several recognizedmethods, such as in vitro methods, animal models, or human clinicaltrials. Recognized in vitro models exist for nearly every class ofcondition, including but not limited to cancer, cardiovascular disease,and various immune dysfunction. Similarly, acceptable animal models maybe used to establish efficacy of chemicals to treat such conditions.When selecting a model to determine efficacy, the skilled artisan can beguided by the state of the art to choose an appropriate model, dose, androute of administration, and regime. Of course, human clinical trialscan also be used to determine the efficacy of a compound in humans.

EXAMPLES

Embodiments are disclosed in further detail in the following examples,which are not in any way intended to limit the scope of the claims.

General Experimental Procedures.

NMR spectra were collected using a 500 MHz Bruker Avance spectrometerusing an inverse probe equipped with x,y,z-gradients, except for the ¹³CNMR spectra, which were acquired with a broad-band observe probe. Datawere acquired at 298K in CDCl₃ referencing 7.24 ppm and 77.00 ppm orDMSO-d6 referencing 2.49 ppm and 39.00 ppm for ¹H and ¹³C-NMRrespectively. The LC-MS data were obtained from an Agilent HP1100 HPLCequipped with an Agilent PDA detector (the mobile phase was a mixture ofCH₃CN and H₂O) and MSD system. Semi-preparative HPLC was performed on aGilson HPLC equipped with a Gilson 215 fraction collector, Agilent PDAdetector and/or ELSD (Sedere) detector. HPLC solvents were obtained fromFisher Scientific and VWR. Deuterated solvents were obtained fromCambridge Isotope Laboratories, Inc. All other chemical reagents wereobtained from Sigma-Aldrich,

Example 1

Sodium iodide (325 mg, 2.2 mmol) was added to a solution of 1 (78 mg,0.22 mmol) in acetone and stirred at room temperature for 48 hours. Thesolution was then concentrated under a stream of nitrogen and thisconcentrated solution was run on a silica plug, in order to removeexcess salts. A composition of 25% EtOAc/hexanes (25 mL) followed by 50%EtOAc/hexanes (200 mL) was used to elute 2 (74.9 mg, 84%).

Example 2

To a solution of compound 2 (40 mg, 0.099 mmol) in dry THF (4 mL) in the20 mL amber vial was added AgF (18.8 mg, 0.15 mmol). The reactionmixture was stirred at room temperature for 16 hours, then filteredthrough a 0.45 micron syringe filter and concentrated. The reactionmixture was purified on reversed phase HPLC using an ACE 5μ C18 HPLCcolumn of dimensions 22 mm id by 150 mm length at a flow rate of 14.5mL/min. Solvent A consisted of water with 0.05% TFA and solvent Bconsisted of acetonitrile with 0.05% TFA and were used as follows: Aninitial gradient of 95% solvent A/5% solvent B increased linearly to 60%solvent A/40% solvent B over 18 minutes; this composition was then heldfor 8 minutes followed by a one minute ramp to 100% solvent B, which washeld for 6 minutes before returning to the initial conditions. Thepurification was monitored by diode array detection (DAD), and 3 elutedat 16 min. Compound 3 was concentrated under reduced pressure (bathtemperature<40° C.) after each injection in order to minimizehydrolysis. Compound 3 (11 mg, 15%) was obtained as a pure compound andconfirmed by spectroscopic data that was identical to those of materialsynthesized by alternative methods, including those described herein.

Example 3

Preparation of AgF supported on CaF₂ (AgF—CaF₂): Silver fluoride wassupported on calcium fluoride by slowly evaporating a mixture of silvercarbonate (3.75 g) dissolved in water (5 mL), 48% aqueous HF (1.2 g, 1.2mL) and calcium fluoride (15 g) to dryness in a 45 mL plastic vial at50° C. in the dark for 2 hours. The reagent was further dried on freezedryer for 15 hours to remove any traces of water. The final reagent wasa brown free-flow granular powder, highly hygroscopic and lightsensitive.

1 g of AgF—CaF₂ was activated by heating at 40° C. under vacuum in around bottom flask with a magnetic stir bar for 30 minutes, to which asolution of Salinosporamide A (250 mg, 0.8 mmol dissolved in 25 mL ofdry CH₂Cl₂) was added and stirred at the same temperature for 18 hours.The solvent was removed under reduce pressure and the resulting residuewas purified by silica flash using a solvent gradient of 50%EtOAc/hexanes, 75% EtOAc/Hexane, 100% EtOAc, 20% methanol/EtOAc and 40%methanol/EtOAc. Compound 3 was eluted in 20-40% methanol/EtOAc fractionsas a pure compound (83 mg, 35% yield). ESIMS, m/z 296 [M+H]⁺.

Example 4

To a solution of compound 3 (17 mg, 0.058 mmol) in dry CH₂Cl₂ (5 mL) wasadded Et₃N (36 μL, 0.26 mmol) and dansyl chloride (78.5 mg, 0.29 mmol)and the solution was stirred at room temperature for 24 hours.Additional dansyl chloride (78.5 mg, 0.29 mmol) and Et₃N (36 μL, 0.26mmol) were added and the reaction was stirred at room temperatureovernight. At 42 hours, the reaction was concentrated under reducedpressure, redissolved in 5 mL of ACN and purified on reversed phase HPLCusing an ACE 5μ C18 column (22 mm×150 mm) at a flow rate of 14.5 mL/min.A solvent gradient of 100% water to 35% acetonitrile/65% water over 8minutes, holding at this solvent composition for 2 minutes and thenlinear gradient increasing to 100% acetonitrile over 5 min, which wasthen held at 100% acetonitrile for 6 min before returning to 100% waterwas used to purify 4. The purification was monitored by diode arraydetection (DAD) and 4 eluted as a pure compound at 15 minutes (17 mg,0.032 mmol, 55.3%). HRESIMS m/z 529.1993 [M+H]⁺ (calcd for C₂₇H₃₃N₂O₇S,529.2008), ¹H NMR (DMSO-d₆); δ 1.18 (br m, 1H), 1.38 (br m, 1H), 1.46(s, 3H), 1.74 (br m, 4H), 1.90 (m, 2H), 2.19 (m, 1H), 2.42 (t, J=7.3 Hz1H), 2.84 (s, 6H, dansyl), 3.60 (t, J=9.5 Hz, 1H), 4.29 (m, 2H), 5.47(d, J=7.9 Hz, C-5 (OH)), 5.73 (m, 2H), 7.29 (d, J=7.6 Hz, 1H, dansyl),7.67 (m, 2H, dansyl), 8.11 (d, J=8.8 Hz, 1H, dansyl), 8.26 (dd, J=1.3,7.3 Hz, 1H, dansyl), 8.59 (d, J=8.8 Hz, 1H, dansyl), 8.99 (s, NH).

Example 5

To a solution of compound 3 (10 mg, 0.034 mmol) in dry CH₂Cl₂ (3.5 mL)was added Et₃N (48 μL, 0.34 mmol) and biphenyl-4-sulfonyl chloride (80mg, 0.32 mmol) and the solution was stirred at room temperature for 18hours. The reaction was concentrated under reduced pressure, redissolvedin 2 mL of ACN and purified by reversed phase HPLC using an ACE 5μ C18column (22 mm id×150 mm length) at a flow rate of 14.5 mL/min using thefollowing solvent gradient: 10% ACN/water to 90% ACN/water over 18minutes, then increasing to 100% ACN over 1 minute, and holding at thissolvent composition for 5 minutes. The purification was monitored bydiode array detection (DAD). The product, compound 5, eluted at 13.5minutes and was concentrated under reduced pressure to yield 7 mg ofproduct (80% pure). The product was further purified using a slightlymodified gradient, i.e. 10% ACN/water to 80% ACN/water over 11 minutes,holding at this solvent composition for 3 min, then increasing to 100%ACN over 1 minute, and holding at this solvent composition for 5minutes. Compound 5 eluted at 13.5 minutes and was concentrated underreduced pressure to yield pure compound 5 (4.5 mg, 26%). ¹H NMR (CDCl₃,500 MH_(z)); δ 1.51-1.60 (ca, 2H), 1.74 (s, 3H), 1.74-1.87 (ca, 2H),1.98-2.15 (ca, 4H), 2.44 (m, 1H), 2.64 (t, J=7.0 Hz 1H), 3.85 (t, J=7.4Hz, 1H), 4.31 (m, 1H), 4.46 (m, 1H), 5.66 (br d, J=10.4 Hz, 1H), 5.98(m, 1H), 6.84 (s, 1H, NH), 7.42 (t, J=7.4 Hz, 1H, biphenyl), 7.47 (t,J=7.4 Hz, 2H, biphenyl), 7.59 (d, J=7.4 Hz, 2H, biphenyl), 7.75 (d,J=8.0 Hz, 2H, biphenyl), 7.96 (d, J=8.0 Hz, 2H, biphenyl); ¹³C NMR(CDCl_(3′) 125 MH_(z)); δ 176.5, 167.1, 147.0, 139.0, 134.3, 133.3,129.1 (2×CH), 128.8, 128.4 (2×CH), 128.0 (2×CH), 127.4 (2×CH), 124.1,85.5, 78.5, 70.3, 67.7, 44.0, 38.0, 26.8, 24.9, 24.6, 20.7, 19.5); ESIMSm/z 512 [M+H]⁺.

Example 6

To a solution of compound 3 (12 mg, 0.041 mmol) in dry CH₂Cl₂ (3.5 mL)was added Et₃N (58 μL, 0.41 mmol) and biphenyl-4-sulfonyl chloride (110mg, 0.30 mmol), and the solution was stirred at room temperature for 18hours. The reaction was concentrated under reduced pressure, redissolvedin 2 mL of ACN and purified by reversed phase HPLC using an ACE 5μ C18column (22 mm×150 mm) at a flow rate of 14.5 mL/min using the followingsolvent gradient: 10% ACN/water to 90% ACN/water over 18 minutes, thenincreasing to 100% ACN over 1 minute, and holding at this solventcomposition for 5 minutes. The purification was monitored by diode arraydetection (DAD). The product, compound 6, eluted at 13.0 minutes and wasconcentrated under reduced pressure to yield 88% pure compound. Theproduct was further purified using slightly modified gradient, i.e. 10%ACN/water to 80% ACN/water over 11 minutes, holding at this solventcomposition for 3 min, then increasing to 100% ACN over a minute, andholding at this solvent composition for 5 minutes. Compound 6 eluted at13.25 minutes and was concentrated under reduced pressure to yield purecompound 6 (2.6 mg, 12%). ¹H NMR (CDCl₃, 500 MH_(z)); δ 1.51-1.60 (m,2H), 1.75 (s, 3H), 1.74-1.87 (m, 2H), 1.98-2.15 (m, 4H), 2.47 (m, 1H),2.63 (t, J=7.2 Hz, 1H), 3.88 (d, J=5.7 Hz, 1H), 4.27 (m, 1H), 4.40 (m,1H), 5.65 (br dd, J=2.5, 10.0 Hz, 1H), 6.00 (m, 1H), 6.54 (s, 1H, NH),7.03-7.09 (m, 4H, phenoxyphenyl), 7.22 (t, J=8 Hz, H, phenoxyphenyl),7.41 (br t, J=8 Hz, 2H, phenoxyphenyl), 7.83 (br d, J=8.0 Hz, 4H,phenoxyphenyl); ¹³C NMR (CDCl_(3′) 125 MH_(z)); δ 176.2, 167.1, 162.7,154.8, 133.6, 130.3 (2×CH), 130.2 (2×CH), 129.0, 125.3, 123.9, 120.5(2×CH), 117.7 (2×CH), 85.6, 78.4, 70.2, 67.4, 44.0, 38.0, 26.9, 24.9,24.6, 20.7, 19.5; ESIMS m/z 528 [M+H]⁺.

Example 7

To a solution of compound 3 (20 mg, 0.068 mmol) in dry CH₂Cl₂ (4 mL) wasadded Et₃N (96 μL, 0.68 mmol) and 4-t-butylphenylsulfonyl chloride (158mg, 0.68 mmol), and the solution was stirred at room temperature for 4hours. The reaction was concentrated under reduced pressure, redissolvedin 3 mL of ACN and purified by reversed phase HPLC using an ACE 5μ C18column (22 mm×150 mm) at a flow rate of 14.5 mL/min using the followingsolvent gradient: 10% ACN/water to 80% ACN/water over 11 minutes,holding at this solvent composition for 3 min, then increasing to 100%ACN over a minute, and holding at this solvent composition for 5minutes. The purification was monitored by diode array detection (DAD).The product, compound 7, eluted at 13.5 minutes and was concentratedunder reduced pressure to yield 90% pure compound (7.3 mg) which wasfurther purified using normal phase silica plug column and 100% CH₂Cl₂(3 mL), 30% EtOAc/hexanes (6 mL), 50% EtOAc/hexanes (6 mL) and 100%EtOAc (10 mL) gradient. The pure compound, compound 7, was eluted in 30%EtOAc/hexanes which was concentrated under reduced pressure to yieldcolorless solid of compound 7 (1.6 mg, 4.8%). ¹H NMR (CDCl₃, 500MH_(z)); δ 1.33 (s, 9H, t-Bu), 1.51-1.62 (m, 4H), 1.73 (s, 3H),1.75-1.87 (m, 2H), 1.98-2.06 (m, 2H), 2.09 (m, 1H), 2.46 (m, 1H), 2.66(t, J=7.2 Hz, 1H), 3.88 (d, J=5.7 Hz, 1H), 4.25 (m, 1H), 4.40 (m, 1H),5.64 (br dd, J=2.5, 10.0 Hz, 1H), 6.01 (m, 1H), 6.44 (s, 1H, NH), 7.55(br d, J=8.5 Hz, 2H), 7.82 (br d, J=8.5 Hz, 2H); ¹³C NMR (CDCl_(3′) 125MH_(z)); δ 176.1, 167.1, 158.0, 133.8, 132.6, 127.8 (2×CH), 126.4(2×CH), 123.7, 85.6, 78.2, 70.1, 67.4, 43.9, 37.9, 35.3, 31.0 (t-Bu),26.9, 24.9, 24.6, 20.6, 19.5; ESIMS m/z 492 [M+H]⁺.

Example 8

To a solution of compound 3 (20 mg, 0.068 mmol) in dry CH₂Cl₂ (3 mL) wasadded pyridine (200 μL, 0.41 mmol) and stirred for 5 min. The reactionmixture was cooled to 0° C. and then added biphenyl-4-carbonyl chloride(30 mg, 0.14 mmol) in dry CH₂Cl₂ (1 mL). The reaction mixture was warmedto room temperature and stirred for 3 hours. The reaction mixture wasconcentrated under reduced pressure, redissolved in 2 mL of ACN andpurified by reversed phase HPLC using an ACE 5μ C18 column (22 mm×150mm) at a flow rate of 14.5 mL/min using the following solvent gradient:10% ACN/water to 80% ACN/water over 11 minutes, holding at this solventcomposition for 3 min, then increasing to 100% ACN over a minute, andholding at this solvent composition for 5 minutes. The product, compound8, eluted at 14.0 minutes and was concentrated under reduced pressure toyield pure compound 8 (3.4 mg, 10.5%). ¹H NMR (CDCl₃, 500 MH_(z)); δ1.50-1.63 (m, 2H), 1.81 (s, 3H), 1.76-1.91 (m, 2H), 2.02 (br m, 2H),2.18 (m, 1H, 12-Hb), 2.31 (m, 1H, 12-Ha) 2.51 (m, 1H, 6-H), 2.69 (t,J=7.2 Hz, 1H, 2-H), 3.91 (br d, J=4.4 Hz, 1H, 5-H), 4.59 (br t, J=6.4Hz, 2H, 13-H₂), 5.68 (br dd, J=2.2, 10.0 Hz, 1H, 7-H), 6.01 (m, 1H,8-H), 6.73 (s, 1H, NH), 7.38 (br t, J=7.2 Hz, 1H), 7.45 (t, J=7.2 Hz,2H), 7.60 (br t, J=7.2 Hz, 2H), 7.65 (br d, J=8.2 Hz, 2H) and 8.08 (brd, J=8.2 Hz, 2H); ¹³C NMR (CDCl_(3′) 125 MH_(z)); δ 176.7, 167.3, 166.2,145.9, 139.9, 133.6, 130.1 (2×CH), 128.9 (2×CH), 128.7, 128.2, 127.3(2×CH), 127.1 (2×CH), 123.9, 85.7, 78.5, 70.3, 62.3, 45.3, 38.0, 26.9,24.9, 24.4, 20.7, 19.9; ESIMS m/z 476 [M+H]⁺.

Example 9

To a solution of compound 3 (50 mg, 0.17 mmol) in dry CH₂Cl₂ (4 mL) wasadded Et₃N (118 μL, 0.85 mmol) and 4-(Chlorosulfonyl)benzoic acid (182mg, 0.85 mmol) and stirred at room temperature for 16 hours under N₂atmosphere. Added more Et₃N (118 μL, 0.85 mmol) and stirred foradditional 4 hours. The reaction mixture was concentrated under reducedpressure, re-dissolved in ACN and DMSO (1:1; 2 mL) and purified onreversed phase HPLC using Ace 5μ C18 column (22 mm×150 mm) and solventgradient of 5% Acetonitrile, 95% water to 100% Acetonitrile over 17minutes, holding at 100% acetonitrile for 3 min, at a flow rate of 14.5mL/min. 0.05% of TFA was added to both water and Acetonitrile mobilephase. The purification was monitored by diode array detector (DAD). Theproduct, compound 9, was eluted as a pure compound 9 (12 mg, 0.025 mmol,15%). ¹H NMR (DMSO-d₆, 500 MH_(z)); 1.21 (m, 1H), 1.40 (m, 1H), 1.69 (m,1H), 1.74 (s, 3H), 1.83 (m, 1H), 1.91 (brs, 2H), 2.05 (m, 3H), 2.28 (m,1H), 2.70 (t, J=7.0 Hz, 1H), 3.67 (d, J=9.5 Hz, 1H), 4.49 (m, 2H), 5.71(br dd, J=2.5, 10.5 Hz, 1H), 5.80 (br d, J=10.5 Hz, 1H), 7.71 (d, J=8.0Hz, 2H, phenyl), 7.94 (d, J=8.0 Hz, 2H, phenyl), 9.09 (brs, 1H, NH); ¹³CNMR (DMSO-d₆, 125 MH_(z)); δ 175.5, 168.6, 165.3, 129.4, 128.9 (2×CH),128.5, 127.7, 125.8 (2×CH), 125.8, 85.6, 78.9, 69.0, 62.6, 45.0, 37.7,25.3, 24.6, 23.7, 21.0, 19.3; ESIMS m/z 480 [M+H]⁺.

Example 10

To a solution of compound 3 (12 mg, 0.041 mmol) in anhydrous pyridine(40 μL, 0.08 mmol) was added acetic anhydride (40 μL) and stirred thereaction mixture for 3 hours at room temperature. Then the reaction wasquenched by adding some tiny ice cubes and extracted with EtOAc (3×3mL). The combined organic layer was concentrated by a stream of nitrogento yield a crude product of compound 10. The crude was re-dissolved in 2mL ACN and purified by reversed phase HPLC using an ACE 5μ C18 column(22 mm×150 mm) at a flow rate of 14.5 mL/min using the following solventgradient: 10% ACN/water to 90% ACN/water over 14 minutes, thenincreasing to 100% ACN over 1 minute, and holding at this solventcomposition for 5 minutes. The purification was monitored by diode arraydetection (DAD). The product, compound 10, eluted at about 8.0 minutesand was concentrated under reduced pressure to yield about 80% pureproduct which was further purified using the same HPLC method. The purefraction was concentrated by reduced pressure to yield a colorless solidof compound 10 (1.2 mg, 8.7%). ¹H NMR (CDCl₃, 500 MH_(z)); δ 1.50-1.65(m, 2H), 1.78 (s, 3H), 1.79-1.90 (m, 2H), 1.96-2.06 (br m, 3H), 2.05 (s,3H), 2.14 (m, 1H), 2.50 (m, 1H, 6-H), 2.58 (t, J=7.0 Hz, 1H, 2-H), 3.90(br d, J=5.7 Hz, 1H, 5-H), 4.32 (br t, J=6.4 Hz, 2H, 13-H₂), 5.66 (brdd, J=2.2, 10.0 Hz, 1H, 7-H), 6.02 (m, 1H, 8-H), 6.47 (s, 1H, NH); ¹³CNMR (CDCl_(3′) 125 MH_(z)); δ 176.5, 170.8, 167.3, 133.8, 123.8, 85.7,78.3, 70.3, 61.7, 45.1, 37.9, 27.0, 24.9, 24.2, 20.9, 20.7, 19.8; ESIMSm/z 338 [M+H]⁺.

Example 11 In Vitro Purified Rabbit Muscle 20S Proteasome ActivityAssays

The chymotrypsin-like activity of the 20S proteasome was determinedessentially as described in Macherla et al J. Med. Chem., 2005, 48 (11),pp 3684-3687. Serial diluted test compounds were added in duplicate to 1μg/ml purified rabbit 20S proteasome in assay buffer containing 20 mMHEPES, pH7.3, 0.5 mM EDTA, 0.05% Triton X-100 and 0.035% SDS andpre-incubated for 5 min at 37° C. Reactions were initiated by theaddition of the Suc-LLVY-AMC peptide substrate at a final concentrationof 20 μM. Fluorescence of the cleaved peptide substrate was measured atλ_(ex)=390 nm and λ_(em)=460 nm using a Fluoroskan Ascent 96-wellmicroplate reader (Thermo Electron, Waltham, Mass.). The IC₅₀ values(the drug concentration at which 50% of the maximal relativefluorescence is inhibited) were calculated by Prism (GraphPad Software)using a sigmoidal dose-response, variable slope model. The caspase-likeactivity of the 20S proteasome was determined as described above exceptthat Z-LLEAMC was used as the peptide substrate. For the evaluation ofthe trypsin-like activity, the SDS was omitted from the assay buffer andBoc-LRR-AMC was used as the peptide substrate.

TABLE 2 INHIBITION OF THE CT-L, T-L AND C-L ACTIVITIES OF 20SPROTEASOMES FROM RABBIT (UNLESS OTHERWISE INDICATED) AND β-LACTONEHYDROLYSIS RATES (T_(1/2)) FOR SALINOSPORAMIDE A AND ANALOGS

Cytotoxicity in RPMI 8226 T_(1/2) Average IC₅₀ ± SD CT-L T-L C-L RLeaving Group (h:min) (nM) IC₅₀ (nM) IC₅₀ (nM) IC₅₀ (nM) CH₂CH₂F 875 ±430  10 ± 0.7 525 ± 15  781 ± 47  CH₂CH₂Cl Yes 1:17 ± 5 9.8 ± 3   2.5 ±1.2 25 ± 4  334 ± 31  CH₂CH₂Br Yes 1:20 7.8 ± 1.4 2.6 ± 0.4 14 ± 2  290± 60  CH₂CH₂I Yes 1:32 6.9 ± 0.9 2.8 ± 0.5 13 ± 3  410 ± 230 CH₂CH₂OMsYes 0:59 144 ± 46  4.3 ± 0.8 65 ± 8  873 ± 32  CH₂CH₂OTs Yes 1:15  27 ±8.5 2.5 ± 0.4 9.9 ± 0.2 127 ± 5 

Yes 94 ± 18 3.2 ± 0.4 31 ± 1  180 ± 4 

Yes 43 ± 12 3.8 ± 0.1 15 ± 1  101 ± 11 

Yes 78 ± 25 3.2 ± 0.2 14 ± 1  85 ± 9  CH₂CH₂ODs Yes 2:59 30 ± 6  3.0 ±0.5  12 ± 2.3 90 ± 11 CH₃ No 1:35 6,300 ± 4,100 7.5 ± 0.6 370 ± 44  460± 49  CH₂CH₃ No 3:10 6,300 ± 3,200  26 ± 6.7 610 ± 35  1200 ± 110 CH₂CH₂CH₃ No 2:51 6,300 ± 3,100 24 ± 5  1100 ± 200  1200 ± 200  CH₂CH₂OHNo 1:25 38,000 ± 4,000   14 ± 1.5 1200 ± 150  1200 ± 57  CH₂CH₂OC(O)CH₃No 20,000 ± 12,000 9.1 ± 0.3 745 ± 40  971 ± 56 

No 290 ± 108 9 ± 2 52 ± 5  160 ± 9  IC₅₀ values represent the mean ±standard deviation of 3 or more experiments

As shown by the data in Table 2, compounds that bear a bulky group atthe R position are potent inhibitors of all three proteolyic subunits(CT-L, C-L and T-L). Notably, compounds with bulky sulfonate estergroups (e.g., dansyl ester or biphenyl ester) or carboxylic ester groupsdemonstrated markedly lower IC₅₀ values for inhibiting the C-L activity.Additionally, the data indicates that the steric bulk of the sulfonateester and carboxylic ester are accommodated within the three ligandbinding sites. As shown by the data, the caspase site tolerates thebulky R group.

The determination of all three rabbit 20S proteolytic activities foradditional compounds with sulfonate esters, carboxylic esters and ethersare determined in a similar manner as described above. As with thedansyl and biphenyl analogs, compounds with bulky sulfonate esters arepotent inhibitors of all three proteolyic subunits. Similarly, compoundswith bulky carboxylic ester and ether groups are also potent inhibitorsof the proteolyic subunits. Additionally, the IC₅₀ values for inhibitingthe C-L activity are lower compared to analogs of Salinosporamide A thathave less bulky groups.

Example 12 Dialysis Studies

Rabbit 20S proteasomes were pretreated for 1 hour with the testcompounds at their respective IC₅₀ values. CT-L activity was measuredbefore and after attempted removal of the compound by dialysis at roomtemperature.

As shown in FIG. 1, as the size of the R¹ group increases, the recoveryof the CT-L activity becomes less. These results indicate that as the R¹group increases, the compound demonstrates prolonged inhibition of the20S proteasome.

Example 13 In Vitro Biology

The test compounds are screened using the National Cancer Institute(NCI) screening panel, which consists of 60 human tumor cell lines thatrepresent leukemia, melanoma and cancers of the lung, colon, brain,ovary, breast, prostate and kidney. A detailed description of thescreening procedure can be found at hypertext transfer protocol<http://www.dtp.nci.nih.gov/branches/btb/ivclsp.html>.

In brief, each of the 60 human tumor cell lines are grown in RPMI 1640medium, supplemented with 5% fetal bovine serum and 2 mM L-glutamine.Cells are plated at their appropriate density in 96-well microtiterplates and are incubated at 37° C., 5% CO₂, 95% air and 100% relativehumidity. After 24 hours, 100 μL of various 10-fold serial dilutions ofthe test compound are added to the appropriate wells containing 100 μLof cells, resulting in a final concentration of the test compoundranging from 10 nM to 100 μM. Cells are incubated for an additional 48hours and a sulforhodamine B protein assay is used to estimate cellviability or growth.

Three dose response parameters are calculated as follows:

-   -   GI₅₀ indicates the concentration that inhibits growth by 50%.    -   TGI indicates the concentration that completely inhibits growth.    -   LC₅₀ indicates the concentration that is lethal to 50% of the        cells.

Test compounds of Formula (I) are effective against the cell lines ofthe 60 human tumor cell lines panel.

Example 14 Growth Inhibition of Tumor Cell Lines

B16-F10 (ATCC; CRL-6475), DU 145 (ATCC; HTB-81), HEK293 (ATCC;CRL-1573), HT-29 (ATCC; HTB-38), LoVo (ATCC; CCL-229), MDA-MB-231 (ATCC;HTB-26), MIA PaCa-2 (ATCC; CRL-1420), NCI-H292 (ATCC; CRL-1848), OVCAR-3(ATCC, HTB-161), PANC-1 (ATCC; CRL-1469), PC-3 (ATCC; CRL-1435), RPMI8226 (ATCC; CCL-155) and U266 (ATCC; TIB-196) are maintained inappropriate culture media. The cells are cultured in an incubator at 37°C. in 5% CO₂ and 95% humidified air.

For cell growth inhibition assays, B16-F10, DU 145, HEK293, HT-29, LoVo,MDA-MB-231, MIA PaCa-2, NCI-H292, OVCAR-3, PANC-1, PC-3, RPMI 8226 andU266 cells are seeded at 1.25×10³, 5×10³, 1.5×10⁴, 5×10³, 5×10³, 1×10⁴,2×10³, 4×10³, 1×10⁴, 7.5×10³, 5×10³, 2×10⁴, 2.5×10⁴ cells/wellrespectively in 90 μl complete media into Corning 3904 black-walled,clear-bottom tissue culture plates. 20 mM stock solutions of the testcompound are prepared in 100% DMSO, aliquoted and stored at −80° C. Thetest compound is serially diluted and added in triplicate to the testwells that result in final concentrations ranging from of 20 μM to 0.2pM. The plates are returned to the incubator for 48 hours. The finalconcentration of DMSO is 0.25% in all samples.

Following 48 hours of drug exposure, 10 μl of 0.2 mg/ml resazurin(obtained from Sigma-Aldrich Chemical Co.) in Mg²⁺, Ca²⁺ free phosphatebuffered saline are added to each well and the plates are returned tothe incubator for 3-6 hours. Since living cells metabolize Resazurin,the fluorescence of the reduction product of Resazurin is measured usinga Fusion microplate fluorometer (Packard Bioscience) with λ_(ex)=535 nmand λ_(em)=590 nm filters. Resazurin dye in medium without cells is usedto determine the background, which was subtracted from the data for allexperimental wells. The data is normalized to the average fluorescenceof the cells treated with media+0.25% DMSO (100% cell growth) and EC₅₀values (the drug concentration at which 50% of the maximal observedgrowth inhibition is established) are determined using a standardsigmoidal dose response curve fitting algorithm (generated by XLfit 3.0,ID Business Solutions Ltd or Prism 3.0, GraphPad Software Inc).

Test compounds of Formula (I) are effective in inhibiting the growthB16-F10, DU 145, HEK293, HT-29, LoVo, MDA-MB-231, MIA PaCa-2, NCI-H292,OVCAR-3, PANC-1, PC-3, RPMI 8226 and U266 cells.

Example 15 Multi-Drug Resistant Cell Lines MES-SA/Dx5 and HL-60/MX2

The EC₅₀ values of the test compound against the human uterine sarcomaMES-SA cell line and its multidrug-resistant derivative MES-SA/Dx5 aredetermined to evaluate whether the test compound retains activityagainst a cell line overexpressing the P-glycoprotein efflux pump.Paclitaxel, a known substrate for the P-glycoprotein pump is included asa control.

The test compound is evaluated against HL-60/MX2, the drug resistantderivative of the human leukemia cell line, HL-60, characterized byhaving a reduced Topoisomerase II activity and considered to haveatypical multidrug resistance. EC₅₀ values for growth inhibition aredetermined for the test compound against the HL-60 and HL-60/MX2. TheDNA binding agent Mitoxantrone is included as a control, as HL-60/MX2cells are reported to be resistant to this chemotherapeutic agent(Harker W. G. et al. 1989).

Test compounds of Formula (I) are effective against the multi drugresistant cell lines MES-SA/Dx5 and HL-60/MX2.

Example 16 Antimicrobial Assays

Minimum inhibitory concentrations (MICs) are determined according to theNational Committee for Clinical Laboratory Standards (NCCLS)susceptibility test guideline M7-A5 (Ferraro, M. 2001 Methods forDilution Antimicrobial Susceptibility Tests for Bacteria that GrowAerobically; Approved Standard (NCCLS). National Committee for ClinicalLaboratory Standards (NCCLS), Villanova, which is incorporated herein byreference in its entirety).

Test compounds of Formula (I) are effective against the microbs tested.

Example 17 Anti-Inflammatory Experiment Inhibition of NF-κB-MediatedLuciferase Activity; HEK293 NF-κB/Luciferase Reporter Cell Line

The HEK293 NF-κB/luciferase reporter cell line is a derivative of thehuman embryonic kidney cell line (ATCC; CRL-1573) and carries aluciferase reporter gene under the regulation of 5×NF-κB binding sites.The reporter cell line is routinely maintained in complete DMEM medium(DMEM plus 10% (v/v) Fetal bovine serum, 2 mM L-glutamine, 10 mM HEPESand Penicillin/Streptomycin at 100 IU/ml and 10014/ml, respectively)supplemented with 250 μg/ml G418. When performing the luciferase assay,the DMEM basal medium is replaced with phenol-red free DMEM basal mediumand the G418 is omitted. The cells are cultured in an incubator at 37°C. in 5% CO₂ and 95% humidified air.

For NF-κB-mediated luciferase assays, HEK293 NF-κB/luciferase cells areseeded at 1.5×10⁴ cells/well in 90 μl phenol-red free DMEM completemedium into Corning 3917 white opaque-bottom tissue culture plates. Fortest compounds, a 4001.1M starting dilution is made in 100% DMSO andthis dilution is used to generate a 8-point half log dilution series.This dilution series is further diluted 40× in appropriate culturemedium and ten μl aliquots are added to the test wells in triplicateresulting in final test concentrations ranging from 1 μM to 320 pM. Theplates are returned to the incubator for 1 hour. After 1 hrpretreatment, 10 μl of a 50 ng/ml TNF-α solution, is prepared in thephenol-red free DMEM medium is added, and the plates are incubated foran additional 6 hr. The final concentration of DMSO is 0.25% in allsamples.

At the end of the TNF-α stimulation, 100 μl of Steady Lite HTSluciferase reagent (Packard Bioscience) is added to each well and theplates are left undisturbed for 10 min at room temperature beforemeasuring the luciferase activity. The relative luciferase units (RLU)are measured by using a Fusion microplate fluorometer (PackardBioscience). The EC₅₀ values (the drug concentration at which 50% of themaximal relative luciferase unit inhibition is established) arecalculated in Prism (GraphPad Software) using a sigmoidal dose response,variable slope model.

Test compounds of Formula (I) are effective in inhibiting NF-κB activityin this cell-based assay.

Inhibition of NF-κB Activation

NF-κB regulates the expression of a large number of genes important ininflammation, apoptosis, tumorigenesis, and autoimmune diseases. In itsinactive form, NF-κB complexes with IκB in the cytosol and uponstimulation, IκB is phosphorylated, ubiquitinated and subsequentlydegraded by the proteasome. The degradation of IκB leads to theactivation of NF-κB and its translocation to the nucleus. The effects oftest compounds on the activation of NF-κB are evaluated by assessing theNF-κB-mediated luciferase activity in HEK293 NF-κB/Luc cells upon TNF-αstimulation.

Pretreatment of NF-κB/Luc 293 cells with test compounds results in adose-dependent decrease of luciferase activity upon TNF-α stimulation.The mean EC₅₀ values to inhibit NF-κB-mediated luciferase activity aremeasured which demonstrate that the test compounds are able to inhibitNF-κB activity in this cell-based assay.

Test compounds of Formula (I) are effective in inhibiting NF-κBactivation.

It will be understood by those of skill in the art that numerous andvarious modifications can be made without departing from the spirit ofthe present disclosure. Therefore, it should be clearly understood thatthe forms disclosed herein are illustrative only and are not intended tolimit the scope of the present disclosure.

1. A method for treating, alleviating or diagnosing a neoplastic disease comprising administering to a subject a therapeutically effective amount of a compound having the structure of Formula (I), or pharmaceutically acceptable salt, ester or prodrug thereof, wherein Formula (I) has the structure:

wherein: R¹ has a structure selected from the group consisting of:

wherein R⁴ is selected from the group consisting of a mono-substituted, a poly-substituted or an unsubstituted variant of the following residues: aryl, aryl(C₁₋₆ alkyl), heteroaryl, heteroaryl(C₁₋₆ alkyl), heterocyclyl, and heterocyclyl(C₁₋₆ alkyl), wherein R⁴ can be optionally substituted with

wherein A is selected from the group consisting of a mono-substituted, a poly-substituted or an unsubstituted variant of the following residues: heterocyclyl, aryl and heteroaryl; and Z¹ is selected from the group consisting of O, S, N═N, O(CH₂)₁₋₆, S(O)₂N(R¹⁷), S(O)₂N(R¹⁷)(CH₂)₁₋₆, C(═O)N(R¹⁷), N(R¹⁷)C(═O), N(R¹⁷)C(═O)(CH₂)₁₋₆, N(R¹⁷)C(═O)O(CH₂)₁₋₆, S(O)₂, C(═O), (CH₂)₁₋₆C(═O), O(CH₂)₁₋₆C(═O), (CH₂)₁₋₆ N(R¹⁷)C(═O), CH═CH—C(═O)N(R¹⁷), CH═CH—C(═O), O(CH₂)₁₋₆O, O(CH₂)₁₋₆ and N(R^(17a))C(═O)N(R^(17b)), wherein R¹⁷, R^(17a) and R^(17b) are independently selected from the group consisting of H, C₁₋₄ alkyl, a substituted or unsubstituted benzyl, an allyl, and t-butoxycarbonyl (t-BOC); R² is selected from the group consisting of a hydrogen, a halogen, cyano, a mono-substituted, a poly-substituted or an unsubstituted variant of the following residues: C₁-C₁₂ alkyl, C₂-C₁₂ alkenyl, C₂-C₁₂ alkynyl, C₃-C₁₂ cycloalkyl, C₃-C₁₂ cycloalkenyl, C₃-C₁₂ cycloalkynyl, C₃-C₁₂ heterocyclyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, (cycloalkyl)alkyl, (heterocyclyl)alkyl, acyl, acylalkyl, alkyloxycarbonyloxy, carbonylacyl, aminocarbonyl, azido, azidoalkyl, mono-haloalkyl, di-haloakyl, tri-haloalkyl, aminoalkyl, salt of an aminoalkyl, carboxyalkyl, a salt of a carboxyalkyl, alkylamino, a salt of an alkylamino, dialkylamino, a salt of a dialkylamino, alkylthio, arylthio, carboxy, alkoxysulfinyl, thiocyano, boronic acidalkyl, boronic esteralkyl, sulfoalkyl, a salt of a sulfoalkyl, alkoxysulfonylalkyl, sulfooxyalkyl, a salt of a sulfooxyalkyl, alkoxysulfonyloxyalkyl, phosphonooxyalkyl, a salt of a phosphonooxyalkyl, (alkylphosphooxy)alkyl, phosphorylalkyl, a salt of a phosphorylalkyl, (alkylphosphoryl)alkyl, pyridinylalkyl, a salt of a pyridinylalkyl, a salt of a heteroarylalkyl guanidino, a salt of a guanidino, and guanidinoalkyl; R³ is selected from the group consisting of hydrogen, halogen, a mono-substituted, a poly-substituted or an unsubstituted variant of the following residues: C₁₋₆ alkyl, C₃₋₆ cycloalkyl, C₂₋₆ alkenyl, C₃₋₆ cycloalkenyl, aryl, and arylalkyl; n is 1, 2 or 3; E¹ and E³ are each a substituted or unsubstituted heteroatom independently selected from the group consisting of O and S; E² is a substituted or unsubstituted N or —CH₂— group; E⁴ is a substituted or unsubstituted heteroatom selected from the group consisting of O, S and N; E⁵ is NH₂, OH or SH; and provided that when R¹ is

R⁴ has a molecular weight equal to or greater than 92 g/mol; and provided that when R¹ is

R⁴ has a molecular weight equal to or greater than 77 g/mol; wherein the neoplastic disease is a cancer is selected from the group consisting of: breast cancer, sarcoma, leukemia, ovarian cancer, bladder cancer, prostate cancer, colon cancer, rectal cancer, stomach cancer, lung cancer, lymphoma, multiple myeloma, pancreatic cancer, kidney cancer, endocrine cancer, melanoma, skin cancer, angiosarcoma, sinus cancer, esophageal cancer, uretal cancer, liver cancer, angioma, central nervous system (CNS) cancer, Mantle cell lymphoma, low IgM secreting lymphoma, Burkitt's lymphoma, B-NHL and Waldenstrom's Macroglobulinemia.
 2. The method of claim 1, wherein when R¹ is

R⁴ has a molecular weight equal to or greater than 107 g/mol or when R¹ is

R⁴ has a molecular weight equal to or greater than 92 g/mol.
 3. The method of claim 1, wherein when R¹ is

R⁴ has a molecular weight equal to or greater than 122 g/mol or when R¹ is

R⁴ has a molecular weight equal to or greater than 107 g/mol.
 4. The method of claim 1, wherein R¹ has a structure selected from the group consisting of:

wherein: R^(5a), R^(5b), R^(5c), R^(5d), R^(5e), R^(9a), R^(9b), R^(9c), R^(9d), R^(9e), R^(13a), R^(13b), R^(13c), R^(13d) and R^(13e) are each independently selected from the group consisting of: hydrogen, halo, nitro, cyano, a mono-substituted, a poly-substituted or an unsubstituted variant of the following residues: C₁₋₂₄ alkyl, C₂₋₂₄ alkenyl, C₂₋₂₄ alkynyl, mono-haloalkyl, di-haloalkyl, tri-haloalkyl, mono-haloalkoxy, di-haloalkoxy, tri-haloalkoxy, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heterocyclyl, amino, mono-substituted amine, di-substituted amine, alkoxy, acyl, aminoalkyl, salt of an aminoalkyl, carboxyalkyl, a salt of a carboxyalkyl, alkylamino, a salt of an alkylamino, dialkylamino, a salt of a dialkylamino, alkylthio, arylthio, carboxy, alkoxysulfinyl, thiocyano, boronic acidalkyl, boronic esteralkyl, sulfoalkyl, a salt of a sulfoalkyl, alkoxysulfonylalkyl, sulfooxyalkyl, a salt of a sulfooxyalkyl, alkoxysulfonyloxyalkyl, phosphonooxyalkyl, a salt of a phosphonooxyalkyl, (alkylphosphooxy)alkyl, phosphorylalkyl, a salt of a phosphorylalkyl, (alkylphosphoryl)alkyl, pyridinylalkyl, a salt of a pyridinylalkyl, a salt of a heteroarylalkyl guanidino, a salt of a guanidino, and guanidinoalkyl; R^(6a), R^(6b), R^(6c), R^(10a), R^(10b), R^(10c), R^(14a), R^(14b) and R^(14c) are each independently selected from the group consisting of: hydrogen, halo, nitro, cyano, a mono-substituted, a poly-substituted or an unsubstituted variant of the following residues: C₁₋₂₄ alkyl, C₂₋₂₄ alkenyl, C₂₋₂₄ alkynyl, mono-haloalkyl, di-haloalkyl, tri-haloalkyl, mono-haloalkoxy, di-haloalkoxy, tri-haloalkoxy, amino, mono-substituted amine, di-substituted amine, alkoxy, acyl, aminoalkyl, salt of an aminoalkyl, carboxyalkyl, a salt of a carboxyalkyl, alkylamino, a salt of an alkylamino, dialkylamino, a salt of a dialkylamino, alkylthio, arylthio, carboxy, alkoxysulfinyl, thiocyano, boronic acidalkyl, boronic esteralkyl, sulfoalkyl, a salt of a sulfoalkyl, alkoxysulfonylalkyl, sulfooxyalkyl, a salt of a sulfooxyalkyl, alkoxysulfonyloxyalkyl, phosphonooxyalkyl, a salt of a phosphonooxyalkyl, (alkylphosphooxy)alkyl, phosphorylalkyl, a salt of a phosphorylalkyl, (alkylphosphoryl)alkyl, pyridinylalkyl, a salt of a pyridinylalkyl, a salt of a heteroarylalkyl guanidino, a salt of a guanidino, and guanidinoalkyl; R^(7a), R^(7b), R^(7c), R^(11a), R^(11b), R^(11c), R^(15a), R^(15b) and R^(15c) are each independently selected from the group consisting of: hydrogen, halo, nitro, cyano, a mono-substituted, a poly-substituted or an unsubstituted variant of the following residues: C₁₋₂₄ alkyl, C₂₋₂₄ alkenyl, C₂₋₂₄ alkynyl, mono-haloalkyl, di-haloalkyl, tri-haloalkyl, mono-haloalkoxy, di-haloalkoxy, tri-haloalkoxy, amino, mono-substituted amine, di-substituted amine, alkoxy, acyl, aminoalkyl, salt of an aminoalkyl, carboxyalkyl, a salt of a carboxyalkyl, alkylamino, a salt of an alkylamino, dialkylamino, a salt of a dialkylamino, alkylthio, arylthio, carboxy, alkoxysulfinyl, thiocyano, boronic acidalkyl, boronic esteralkyl, sulfoalkyl, a salt of a sulfoalkyl, alkoxysulfonylalkyl, sulfooxyalkyl, a salt of a sulfooxyalkyl, alkoxysulfonyloxyalkyl, phosphonooxyalkyl, a salt of a phosphonooxyalkyl, (alkylphosphooxy)alkyl, phosphorylalkyl, a salt of a phosphorylalkyl, (alkylphosphoryl)alkyl, pyridinylalkyl, a salt of a pyridinylalkyl, a salt of a heteroarylalkyl guanidino, a salt of a guanidino, and guanidinoalkyl; R^(8a), R^(8b), R^(8c), R^(8d), R^(12a), R^(12b), R^(12c), R^(12d), R^(16a), R^(16b), R^(16c) and R^(16d) are each independently selected from the group consisting of: hydrogen, halo, nitro, cyano, a mono-substituted, a poly-substituted or an unsubstituted variant of the following residues: C₁₋₂₄ alkyl, C₂₋₂₄ alkenyl, C₂₋₂₄ alkynyl, mono-haloalkyl, di-haloalkyl, tri-haloalkyl, mono-haloalkoxy, di-haloalkoxy, tri-haloalkoxy, amino, mono-substituted amine, di-substituted amine, alkoxy, acyl, aminoalkyl, salt of an aminoalkyl, carboxyalkyl, a salt of a carboxyalkyl, alkylamino, a salt of an alkylamino, dialkylamino, a salt of a dialkylamino, alkylthio, arylthio, carboxy, alkoxysulfinyl, thiocyano, boronic acidalkyl, boronic esteralkyl, sulfoalkyl, a salt of a sulfoalkyl, alkoxysulfonylalkyl, sulfooxyalkyl, a salt of a sulfooxyalkyl, alkoxysulfonyloxyalkyl, phosphonooxyalkyl, a salt of a phosphonooxyalkyl, (alkylphosphooxy)alkyl, phosphorylalkyl, a salt of a phosphorylalkyl, (alkylphosphoryl)alkyl, pyridinylalkyl, a salt of a pyridinylalkyl, a salt of a heteroarylalkyl guanidino, a salt of a guanidino, and guanidinoalkyl and —S(═O)₂O⁻; B, D and F are each independently selected from the group consisting of a mono-substituted, a poly-substituted or an unsubstituted variant of the following residues: heterocyclyl, aryl, heteroaryl, cycloalkyl and cycloalkenyl; C, E and G are each independently selected from the group consisting of a mono-substituted, a poly-substituted or an unsubstituted variant of the following residues: heterocyclyl, aryl, heteroaryl, cycloalkyl and cycloalkenyl; A is selected from the group consisting of a mono-substituted, a poly-substituted or an unsubstituted variant of the following residues: heterocyclyl, aryl, heteroaryl, cycloalkyl and cycloalkenyl; and Z¹ is selected from the group consisting of O, S, N═N, O(CH₂)₁₋₆, S(O)₂N(R¹⁷), S(O)₂N(R¹⁷)(CH₂)₁₋₆, C(═O)N(R¹⁷), N(R¹⁷)C(═O), N(R¹⁷)C(═O)(CH₂)₁₋₆, N(R¹⁷)C(═O)O(CH₂)₁₋₆, S(O)₂, C(═O), (CH₂)₁₋₆C(═O), O(CH₂)₁₋₆C(═O), (CH₂)₁₋₆N(R¹⁷)C(═O), CH═CH—C(═O)N(R¹⁷), CH═CH—C(═O), O(CH₂)₁₋₆O, O(CH₂)₁₋₆ and N(R^(17a))C(═O)N(R^(17b)), wherein R¹⁷, R^(17a) and R^(17b) are independently selected from the group consisting of H, C₁₋₄ alkyl, a substituted or unsubstituted benzyl, an allyl, and t-butoxycarbonyl (t-BOC).
 5. The method of claim 4, wherein R¹ is

and R^(5a), R^(5b), R^(5c), R^(5d), and R^(5e) are each independently selected from the group consisting of: hydrogen, halo, nitro, a mono-substituted, a poly-substituted or an unsubstituted variant of the following residues: C₁₋₂₄ alkyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, mono-haloalkyl, di-haloalkyl, tri-haloalkyl, mono-haloalkoxy, di-haloalkoxy, tri-haloalkoxy, amino, mono-substituted amine, di-substituted amine, alkoxy, and carboxy.
 6. The method of claim 4, wherein R¹ is

and B is a mono-substituted, a poly-substituted or an unsubstituted aryl ring.
 7. The method of claim 4, wherein R¹ is

and C is a mono-substituted, a poly-substituted or an unsubstituted heterocyclyl ring.
 8. The method of claim 4, wherein R¹ is

and C is a mono-substituted, a poly-substituted or an unsubstituted aryl ring.
 9. The method of claim 4, wherein R¹ is

and Z¹ is O or N═N.
 10. The method of claim 4, wherein R¹ is

and A is a mono-substituted, a poly-substituted or an unsubstituted aryl ring.
 11. The method of claim 4, wherein R¹ is

and A is a mono-substituted, a poly-substituted or an unsubstituted heteroaryl ring.
 12. The method of claim 4, wherein R¹ is

and R^(9a), R^(9b), R^(9c), R^(9d) and R^(9e) are each independently selected from the group consisting of: hydrogen, halo, nitro, cyano, a mono-substituted, a poly-substituted or an unsubstituted variant of the following residues: C₁₋₂₄ alkyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, mono-haloalkyl, di-haloalkyl, tri-haloalkyl, mono-haloalkoxy, di-haloalkoxy, tri-haloalkoxy, amino, mono-substituted amine, di-substituted amine, alkoxy, and hydroxy.
 13. The method of claim 4, wherein R¹ is

and D is a mono-substituted, a poly-substituted or an unsubstituted aryl ring.
 14. The method of claim 4, wherein R¹ is

and E is a mono-substituted, a poly-substituted or an unsubstituted aryl ring.
 15. The method of claim 4, wherein R¹ is

and Z¹ is selected from the group consisting of O, O(CH₂)₁₋₆ and N═N.
 16. The method of claim 4, wherein R¹ is

and A is a mono-substituted, a poly-substituted or an unsubstituted aryl ring.
 17. The method of claim 4, wherein R¹ is

R^(13a), R^(13b), R^(13c), R^(13d) and R^(13e) are each independently selected from the group consisting of: hydrogen, halo, nitro, cyano, a mono-substituted, a poly-substituted or an unsubstituted variant of the following residues: C₁₋₂₄ alkyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, mono-haloalkyl, di-haloalkyl, tri-haloalkyl, mono-haloalkoxy, di-haloalkoxy, tri-haloalkoxy, amino, mono-substituted amine, di-substituted amine, alkoxy, carboxy and hydroxy.
 18. The method of claim 4, wherein R¹ is

and F is a mono-substituted, a poly-substituted or an unsubstituted aryl ring.
 19. The method of claim 4, wherein R¹ is

and G is a mono-substituted, a poly-substituted or an unsubstituted aryl ring.
 20. The method of claim 4, wherein R¹ is

and Z¹ is O or N═N.
 21. The method of claim 4, wherein R¹ is

and A is a mono-substituted, a poly-substituted or an unsubstituted aryl ring.
 22. The method of claim 4, wherein: R¹ is selected from the group consisting of:


23. The method of claim 4, wherein: R¹ is selected from the group consisting of:


24. The method of claim 4, wherein R¹ is selected from the group consisting of:


25. The method of claim 1, wherein R³ is selected from the group consisting of a mono-substituted, a poly-substituted or an unsubstituted variant of the following residues: C₁₋₆ alkyl, C₃₋₆ cycloalkyl, C₂₋₆ alkenyl, C₃₋₆ cycloalkenyl, aryl, and arylalkyl.
 26. The method of claim 25, wherein R² is selected from the group consisting of a mono-substituted, a poly-substituted or an unsubstituted C₁-C₁₂ alkyl, a mono-substituted, a poly-substituted or an unsubstituted C₃-C₁₂ cycloalkanyl, a mono-substituted, a poly-substituted or an unsubstituted C₃-C₁₂ cycloalkenyl and a mono-substituted, a poly-substituted or an unsubstituted aryl; and R³ is a mono-substituted, a poly-substituted or an unsubstituted C₁₋₆ alkyl.
 27. The method of claim 26, wherein n is
 2. 28. The method of claim 1, wherein the cancer is selected from the group consisting of multiple myeloma, a colorectal carcinoma, a prostate carcinoma, a breast adenocarcinoma, a non-small cell lung carcinoma, an ovarian carcinoma and a melanoma.
 29. The method of claim 1, wherein the cancer is a drug-resistant cancer.
 30. The method of claim 29, wherein the drug-resistant cancer may display at least one of the following: elevated levels of the P-glycoprotein efflux pump, increased expression of the multidrug-resistance associated protein 1 encoded by MRP1, reduced drug uptake, alteration of the drug's target or increasing repair of drug-induced DNA damage, alteration of the apoptotic pathway or the activation of cytochrome P450 enzymes.
 31. The method of claim 29, wherein the drug-resistant cancer is leukemia or a sarcoma.
 32. A method for inhibiting NF-κB activity comprising administering to a subject a therapeutically effective amount of a compound having the structure of Formula (I), or pharmaceutically acceptable salt, ester or prodrug thereof, wherein Formula (I) has the structure:

wherein: R¹ has a structure selected from the group consisting of:

wherein R⁴ is selected from the group consisting of a mono-substituted, a poly-substituted or an unsubstituted variant of the following residues: aryl, aryl(C₁₋₆ alkyl), heteroaryl, heteroaryl(C₁₋₆ alkyl), heterocyclyl, and heterocyclyl(C₁₋₆ alkyl), wherein R⁴ can be optionally substituted with

wherein A is selected from the group consisting of a mono-substituted, a poly-substituted or an unsubstituted variant of the following residues: heterocyclyl, aryl and heteroaryl; and Z¹ is selected from the group consisting of O, S, N═N, O(CH₂)₁₋₆, S(O)₂N(R¹⁷), S(O)₂N(R¹⁷)(CH₂)₁₋₆, C(═O)N(R¹⁷), N(R¹⁷)C(═O), N(R¹⁷)C(═O)(CH₂)₁₋₆, N(R¹⁷)C(═O)O(CH₂)₁₋₆, S(O)₂, C(═O), (CH₂)₁₋₆C(═O), O(CH₂)₁₋₆C(═O), (CH₂)₁₋₆N(R¹⁷)C(═O), CH═CH—C(═O)N(R¹⁷), CH═CH—C(═O), O(CH₂)₁₋₆O, O(CH₂)₁₋₆ and N(R^(17a))C(═O)N(R^(17b)), wherein R¹⁷, R^(17a) and R^(17b) are independently selected from the group consisting of H, C₁₋₄ alkyl, a substituted or unsubstituted benzyl, an allyl, and t-butoxycarbonyl (t-BOC); R² is selected from the group consisting of a hydrogen, a halogen, cyano, a mono-substituted, a poly-substituted or an unsubstituted variant of the following residues: C₁-C₁₂ alkyl, C₂-C₁₂ alkenyl, C₂-C₁₂ alkynyl, C₃-C₁₂ cycloalkyl, C₃-C₁₂ cycloalkenyl, C₃-C₁₂ cycloalkynyl, C₃-C₁₂ heterocyclyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, (cycloalkyl)alkyl, (heterocyclyl)alkyl, acyl, acylalkyl, alkyloxycarbonyloxy, carbonylacyl, aminocarbonyl, azido, azidoalkyl, mono-haloalkyl, di-haloakyl, tri-haloalkyl, aminoalkyl, salt of an aminoalkyl, carboxyalkyl, a salt of a carboxyalkyl, alkylamino, a salt of an alkylamino, dialkylamino, a salt of a dialkylamino, alkylthio, arylthio, carboxy, alkoxysulfinyl, thiocyano, boronic acidalkyl, boronic esteralkyl, sulfoalkyl, a salt of a sulfoalkyl, alkoxysulfonylalkyl, sulfooxyalkyl, a salt of a sulfooxyalkyl, alkoxysulfonyloxyalkyl, phosphonooxyalkyl, a salt of a phosphonooxyalkyl, (alkylphosphooxy)alkyl, phosphorylalkyl, a salt of a phosphorylalkyl, (alkylphosphoryl)alkyl, pyridinylalkyl, a salt of a pyridinylalkyl, a salt of a heteroarylalkyl guanidino, a salt of a guanidino, and guanidinoalkyl; R³ is selected from the group consisting of hydrogen, halogen, a mono-substituted, a poly-substituted or an unsubstituted variant of the following residues: C₁₋₆ alkyl, C₃₋₆ cycloalkyl, C₂₋₆ alkenyl, C₃₋₆ cycloalkenyl, aryl, and arylalkyl; n is 1, 2 or 3; E¹ and E³ are each a substituted or unsubstituted heteroatom independently selected from the group consisting of O and S; E² is a substituted or unsubstituted N or —CH₂— group; E⁴ is a substituted or unsubstituted heteroatom selected from the group consisting of O, S and N; E⁵ is NH₂, OH or SH; and provided that when R¹ is

R⁴ has a molecular weight equal to or greater than 92 g/mol; and provided that when R¹ is

R⁴ has a molecular weight equal to or greater than 77 g/mol.
 33. A method of inhibiting proteasome activity comprising administering to a subject a therapeutically effective amount of a compound having the structure of Formula (I), or pharmaceutically acceptable salt, ester or prodrug thereof, wherein Formula (I) has the structure:

wherein: R¹ has a structure selected from the group consisting of:

wherein R⁴ is selected from the group consisting of a mono-substituted, a poly-substituted or an unsubstituted variant of the following residues: aryl, aryl(C₁₋₆ alkyl), heteroaryl, heteroaryl(C₁₋₆ alkyl), heterocyclyl, and heterocyclyl(C₁₋₆ alkyl), wherein R⁴ can be optionally substituted with

wherein A is selected from the group consisting of a mono-substituted, a poly-substituted or an unsubstituted variant of the following residues: heterocyclyl, aryl and heteroaryl; and Z¹ is selected from the group consisting of O, S, N═N, O(CH₂)₁₋₆, S(O)₂N(R¹⁷), S(O)₂N(R¹⁷)(CH₂)₁₋₆, C(═O)N(R¹⁷), N(R¹⁷)C(═O), N(R¹⁷)C(═O)(CH₂)₁₋₆, N(R¹⁷)C(═O)O(CH₂)₁₋₆, S(O)₂, C(═O), (CH₂)₁₋₆C(═O), O(CH₂)₁₋₆C(═O), (CH₂)₁₋₆N(R¹⁷)C(═O), CH═CH—C(═O)N(R¹⁷), CH═CH—C(═O), O(CH₂)₁₋₆O, O(CH₂)₁₋₆ and N(R^(17a))C(═O)N(R^(17b)), wherein R¹⁷, R^(17a) and R^(17b) are independently selected from the group consisting of H, C₁₋₄ alkyl, a substituted or unsubstituted benzyl, an allyl, and t-butoxycarbonyl (t-BOC); R² is selected from the group consisting of a hydrogen, a halogen, cyano, a mono-substituted, a poly-substituted or an unsubstituted variant of the following residues: C₁-C₁₂ alkyl, C₂-C₁₂ alkenyl, C₂-C₁₂ alkynyl, C₃-C₁₂ cycloalkyl, C₃-C₁₂ cycloalkenyl, C₃-C₁₂ cycloalkynyl, C₃-C₁₂ heterocyclyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, (cycloalkyl)alkyl, (heterocyclyl)alkyl, acyl, acylalkyl, alkyloxycarbonyloxy, carbonylacyl, aminocarbonyl, azido, azidoalkyl, mono-haloalkyl, di-haloakyl, tri-haloalkyl, aminoalkyl, salt of an aminoalkyl, carboxyalkyl, a salt of a carboxyalkyl, alkylamino, a salt of an alkylamino, dialkylamino, a salt of a dialkylamino, alkylthio, arylthio, carboxy, alkoxysulfinyl, thiocyano, boronic acidalkyl, boronic esteralkyl, sulfoalkyl, a salt of a sulfoalkyl, alkoxysulfonylalkyl, sulfooxyalkyl, a salt of a sulfooxyalkyl, alkoxysulfonyloxyalkyl, phosphonooxyalkyl, a salt of a phosphonooxyalkyl, (alkylphosphooxy)alkyl, phosphorylalkyl, a salt of a phosphorylalkyl, (alkylphosphoryl)alkyl, pyridinylalkyl, a salt of a pyridinylalkyl, a salt of a heteroarylalkyl guanidino, a salt of a guanidino, and guanidinoalkyl; R³ is selected from the group consisting of hydrogen, halogen, a mono-substituted, a poly-substituted or an unsubstituted variant of the following residues: C₁₋₆ alkyl, C₃₋₆ cycloalkyl, C₂₋₆ alkenyl, C₃₋₆ cycloalkenyl, aryl, and arylalkyl; n is 1, 2 or 3; E¹ and E³ are each a substituted or unsubstituted heteroatom independently selected from the group consisting of O and S; E² is a substituted or unsubstituted N or —CH₂— group; E⁴ is a substituted or unsubstituted heteroatom selected from the group consisting of O, S and N; E⁵ is NH₂, OH or SH; and provided that when R¹ is

R⁴ has a molecular weight equal to or greater than 92 g/mol; and provided that when R¹ is

R⁴ has a molecular weight equal to or greater than 77 g/mol.
 34. A method for inhibiting the growth of a cancer cell comprising contacting the cancer cell with a therapeutically effective amount of a compound having the structure of Formula (I), or pharmaceutically acceptable salt, ester or prodrug thereof, wherein Formula (I) has the structure:

wherein: R¹ has a structure selected from the group consisting of:

wherein R⁴ is selected from the group consisting of a mono-substituted, a poly-substituted or an unsubstituted variant of the following residues: aryl, aryl(C₁₋₆ alkyl), heteroaryl, heteroaryl(C₁₋₆ alkyl), heterocyclyl, and heterocyclyl(C₁₋₆ alkyl), wherein R⁴ can be optionally substituted with

wherein A is selected from the group consisting of a mono-substituted, a poly-substituted or an unsubstituted variant of the following residues: heterocyclyl, aryl and heteroaryl; and Z¹ is selected from the group consisting of O, S, N═N, O(CH₂)₁₋₆, S(O)₂N(R¹⁷), S(O)₂N(R¹⁷)(CH₂)₁₋₆, C(═O)N(R¹⁷), N(R¹⁷)C(═O), N(R¹⁷)C(═O)(CH₂)₁₋₆, N(R¹⁷)C(═O)O(CH₂)₁₋₆, S(O)₂, C(═O), (CH₂)₁₋₆C(═O), O(CH₂)₁₋₆C(═O), (CH₂)₁₋₆N(R¹⁷)C(═O), CH═CH—C(═O)N(R¹⁷), CH═CH—C(═O), O(CH₂)₁₋₆O, O(CH₂)₁₋₆ and N(R^(17a))C(═O)N(R^(17b)), wherein R¹⁷, R^(17a) and R^(17b) are independently selected from the group consisting of H, C₁₋₄ alkyl, a substituted or unsubstituted benzyl, an allyl, and t-butoxycarbonyl (t-BOC); R² is selected from the group consisting of a hydrogen, a halogen, cyano, a mono-substituted, a poly-substituted or an unsubstituted variant of the following residues: C₁-C₁₂ alkyl, C₂-C₁₂ alkenyl, C₂-C₁₂ alkynyl, C₃-C₁₂ cycloalkyl, C₃-C₁₂ cycloalkenyl, C₃-C₁₂ cycloalkynyl, C₃-C₁₂ heterocyclyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, (cycloalkyl)alkyl, (heterocyclyl)alkyl, acyl, acylalkyl, alkyloxycarbonyloxy, carbonylacyl, aminocarbonyl, azido, azidoalkyl, mono-haloalkyl, di-haloakyl, tri-haloalkyl, aminoalkyl, salt of an aminoalkyl, carboxyalkyl, a salt of a carboxyalkyl, alkylamino, a salt of an alkylamino, dialkylamino, a salt of a dialkylamino, alkylthio, arylthio, carboxy, alkoxysulfinyl, thiocyano, boronic acidalkyl, boronic esteralkyl, sulfoalkyl, a salt of a sulfoalkyl, alkoxysulfonylalkyl, sulfooxyalkyl, a salt of a sulfooxyalkyl, alkoxysulfonyloxyalkyl, phosphonooxyalkyl, a salt of a phosphonooxyalkyl, (alkylphosphooxy)alkyl, phosphorylalkyl, a salt of a phosphorylalkyl, (alkylphosphoryl)alkyl, pyridinylalkyl, a salt of a pyridinylalkyl, a salt of a heteroarylalkyl guanidino, a salt of a guanidino, and guanidinoalkyl; R³ is selected from the group consisting of hydrogen, halogen, a mono-substituted, a poly-substituted or an unsubstituted variant of the following residues: C₁₋₆ alkyl, C₃₋₆ cycloalkyl, C₂₋₆ alkenyl, C₃₋₆ cycloalkenyl, aryl, and arylalkyl; n is 1, 2 or 3; E¹ and E³ are each a substituted or unsubstituted heteroatom independently selected from the group consisting of O and S; E² is a substituted or unsubstituted N or —CH₂— group; E⁴ is a substituted or unsubstituted heteroatom selected from the group consisting of O, S and N; E⁵ is NH₂, OH or SH; and provided that when R¹ is

R⁴ has a molecular weight equal to or greater than 92 g/mol; and provided that when R¹ is

R⁴ has a molecular weight equal to or greater than 77 g/mol; wherein the cancer cell is selected from the group consisting of a breast cancer cell, a sarcoma cell, a leukemia cell, an ovarian cancer cell, a bladder cancer cell, a prostate cancer cell, a colon cancer cell, a rectal cancer cell, a stomach cancer cell, a lung cancer cell, a lymphoma cell, a multiple myeloma cell, a pancreatic cancer cell, a kidney cancer cell, an endocrine cancer cell, a melanoma cell, a skin cancer cell, an angiosarcoma cell, a sinus cancer cell, an esophageal cancer cell, an uretal cancer cell, a liver cancer cell, an angioma cell and a central nervous system (CNS) cancer cell. 